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CN1627944A - Substituted quinazolin-4-ylamine analogs as capsaicin modulators - Google Patents

Substituted quinazolin-4-ylamine analogs as capsaicin modulators Download PDF

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Publication number
CN1627944A
CN1627944A CNA038024527A CN03802452A CN1627944A CN 1627944 A CN1627944 A CN 1627944A CN A038024527 A CNA038024527 A CN A038024527A CN 03802452 A CN03802452 A CN 03802452A CN 1627944 A CN1627944 A CN 1627944A
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trifluoromethyl
pyridin
amine
phenyl
quinazolin
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R·巴克萨瓦奇阿拉姆
C·A·布卢姆
H·L·布里尔曼
T·M·考德威尔
S·德隆贝特
K·J·霍杰茨
T·允
X·郑
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Neurogen Corp
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Neurogen Corp
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Abstract

总的来说本发明是有关经取代的喹唑啉－4－基胺类似物，其为辣椒辣素受体调节剂，以及关于使用此种化合物治疗辣椒辣素受体活化相关疾病的用途。本发明进一步是关于使用此种化合物作为探针来检测与定位辣椒辣素受体。

Figure 03802452

The present invention generally relates to substituted quinazolin-4-ylamine analogs that are capsaicin receptor modulators and the use of such compounds to treat diseases associated with capsaicin receptor activation. The invention further relates to the use of such compounds as probes for the detection and localization of capsaicin receptors.

Figure 03802452

Description

Quinazoline-4-the ylamine analogues that replaces is as modulators of capsaicin
Technical field
Generally speaking the invention relates to the quinazoline-4-ylamine analogues that is substituted, it is the capsaicin receptor modulators, and about using the purposes of this kind compounds for treating capsaicin receptor activation relevant disease.The present invention further is about using this kind chemical compound to detect and locate the capsaicin receptor as probe.
Background technology
Pain perception or be referred to as the pain sensation be by a kind of name into the nerve of special sense of " pain receptor " unit tip vehicular.Mammiferous this kind pain receptor neuronal activation is brought out in multiple widely physical stimulation and chemical stimulation, and the result causes identification possibility destructive stimulus.But improper activation of pain receptor or overactivity may cause muscle power weak acute pain or chronic pain.
Neuropathy degeneration pain is involved in the pain sensation signal transmission under the non-stimulated existence, and it is impaired to come from nervous system typically.Under most of situation, pain be since neural system of periphery and central nervous system after initial perimeter systems damage (for example seeing through directly, injured or systemic disease damages) nervous system by due to the sensitization.The intensity of neuropathy degeneration pain is typically to be burnt, launch, stablizes unrelaxing, and neuropathy degeneration pain may more allow people's physical ability weakness than the injury of bringing out pain at first or lysis once in a while.
Most invalid to neuropathy degeneration pain therapy at present.Opiate for example morphine is the strong pain-relieving agent, but the purposes of Opiate is because its adverse side effect thereby restricted, its adverse side effect for example is the physiology addiction and has the character of giving up, and respiration inhibition, mood change, minimizing intestinal peristalsis promoting are followed constipation, felt sick, vomiting, and change hormonal system and autonomic nervous system.In addition, neuropathy degeneration pain is often reactionless or have only partial reaction to conventional Opium class pain management.Adopt N-methyl D-Radix Asparagi acid esters antagonist ketamine (ketamine) or α (2) epinephrine to swash property agonist clonidine and can reduce acute pain or chronic pain, allow to reduce Opium class consumption, but these medicaments are because side effect cause toleration is not good.
Once use the capsaicin topical therapeutic to handle chronic pain and acute pain, comprised neuropathy degeneration pain.Capsaicin is the peppery property material derived from plant of Solanaceae (comprising Fructus Capsici), and capsaicin obviously is that selectively acting is in little it is believed that to transmitting the afferent nerve fiber (A-Δ fiber and C fiber) of pain of diameter.Response feature to capsaicin is the pain nerve receptor persistence activation of perienchyma, and last peripheral pain receptor is to a kind of stimulation or multiple stimulation desensitization.By zooscopy, capsaicin inspires the depolarization of C fibrous membrane via the cation selective passage of opening calcium and sodium.For stripped sensory neuron, the reaction and display of capsaicin is relevant with dosage.
This kind reaction also can be excited by the capsaicin analog, and the capsaicin analog is enjoyed a total class Rhizoma et radix valerianae part.Wherein a kind of analog is RTX (RTX), belongs to euphorbiaceous natural product.Class Rhizoma et radix valerianae receptor (VR) speech is to create the neuron film identifying position of describing capsaicin and related stimulus chemical compound.The reaction of capsaicin is subjected to the antagonism of the competitive inhibition (therefore by antagonism) of another kind of capsaicin analog capsaicin receptor blocker, and the reaction of capsaicin also is subjected to the inhibition of non-selective cationic channel blocker ammoniated ruthenium oxychloride.These antagonisies are bonded to VR, and affinity is not more than medium affinity, and (typical case has K iValue is not less than 140 μ M).
Recently, go out rat and human capsaicin receptor by the dorsal root ganglion cell clone.This kind receptor is called VR1, and " VR1 " and " capsaicin receptor " speech is in being used interchangeably herein rat and/or human receptor and the mammals homologue of representing this type.VR1 role in the pain sensation has used the mice that lacks this kind pain receptor to obtain to confirm, the pain performance that mice does not have the Rhizoma et radix valerianae element to excite is to thermal response and impaired to the reaction of inflammation.The capsaicin receptor is a kind of non-selective cation channel, and the threshold value that the cation channel is opened is to be lower than the reaction that temperature is risen high and low pH and capsaicin receptor agonists.For example channel normally is being higher than about 45 ℃ of temperature unlatching.The unlatching of capsaicin receptor channel then is to discharge the inflammatory peptide from neuron of expressing this receptor and contiguous neuron usually, and increases pain reaction.After the capsaicin primary activation, the capsaicin receptor desensitizes fast by cAMP dependence protein matter tyrosine phosphorylation.
Because the plain chemical compound of VR1 agonist class Rhizoma et radix valerianae can allow the pain receptor of perienchyma so desensitize, so VR1 agonist class Rhizoma et radix valerianae chemical compound is used as local anesthetic.But the agonist purposes itself causes calcination pain, and therefore limiting it is used for this medical application.
So can with the VR1 reciprocal action, but can not carry the chemical compound of the initial stage pain sensation of drawing VR1 agonist class Rhizoma et radix valerianae chemical compound, for chronic pain and acute pain comprise on the neuropathy degeneration treatment of pain required.The antagonist of this kind receptor needs on pain therapy especially, and to for example being exposed to teargas, scratching where it itches and situation such as urinary incontinence needs especially.The present invention can satisfy this demand and extra associated advantages is provided.
Summary of the invention
The invention provides the capsaicin receptor modulators, it regulates the activation of capsaicin receptor, and preferably suppresses the activation of capsaicin receptor.Aspect some, chemical compound provided herein is feature with the following formula:
Figure A0380245200771
Formula I
Or its pharmaceutically acceptable salt.
Among the formula I, V and X are respectively N or CR separately 1, condition is that among V and the X at least one is for N; U is N or CR 2, but if V and X are N, then U is CR 2W, Y and Z are respectively N or CR separately 1R 1When occurring, be independently selected from hydrogen, halogen atom, hydroxyl, cyano group, amino, C at every turn 1-C 8Alkyl, halo C 1-C 8Alkyl, C 1-C 8Alkoxyl, halo C 1-C 8Alkoxyl and one-(C 1-C 8Alkyl) amino and two-(C 1-C 8Alkyl) amino.
R 2For: (i) hydrogen, halogen atom, cyano group or-COOH; (ii) C 2-C 8Alkoxy carbonyl group, C 1-C 8Alkanoyl, C 2-C 8Alkane ketone, C 1-C 8Alkanoyloxy, C 1-C 8Carbonate or C 1-C 8The carbamic acid root, it is respectively done for oneself and is unsubstituted or by 1 to 9 R bSubstituent group replace; Or (iii) suc as formula-R c-M-A-R yGroup, wherein: R cBe C 0-C 3Alkyl; M is that key connects, N (R z), O, S, SO 2,-C (=O) pN (R z), N (R z) C (=O) p, SO 2N (R z) or N (R z) SO 2, wherein p is 0 or 1; A is the key connection or optionally is selected from R respectively by 1 to 3 bThe C that replaces of substituent group 1-C 8Alkyl; And R yAnd R zBe respectively (a) hydrogen, C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, C 6-C 10Aryl C 1-C 8Alkyl, C 2-C 8Alkyl ether, C 1-C 8Alkoxyl, 4 to 10 unit carbocyclic ring or heterocycles, or be engaged to R cAnd form 4 to 10 unit carbocyclic ring or heterocycles, wherein each R yAnd R zBe respectively and be unsubstituted or be selected from R respectively by 1 to 9 bSubstituent group replace; Or (b) engage and form one 4 to 10 unit heterocycle, it is for being unsubstituted or being selected from R respectively by 1 to 9 bSubstituent group replace.
R bBe respectively to be selected from hydroxyl, halogen atom, amino, amino carbonyl, acylamino-, cyano group, nitro, ketone group, C when each time occurs 1-C 8Alkyl, C 1-C 8Alkoxyl, C 1-C 8Alkylthio group, C 1-C 8Alkyl ether, hydroxyl C 1-C 8Alkyl, halogen C 1-C 8Alkyl, phenyl, phenyl (C 1-C 8Alkyl), one-(C 1-C 6Alkyl) amino and two-(C 1-C 6Alkyl) amino, (SO 2) C 1-C 8Alkyl, 5 yuan to 7 yuan heterocycles reach (5 yuan to 7 yuan heterocycles) (C 1-C 8Alkyl).
Ar 1And Ar 2Be respectively to be selected from 5 yuan to 10 yuan aromatic carbon rings and heterocycle separately, it is respectively done for oneself and is unsubstituted, or is selected from suc as formula LR respectively by 1 to 3 aSubstituent group replace.L when occurring separately be respectively be selected from key connect ,-O-,-C (=O)-,-OC (=O)-,-C (=O) O-,-O-C (=O) O-,-S (O) m-,-NR x-,-C (=O) NHR x-,-NHR xC (=O)-,-NR xS (O) m-, S (O) mNR x-and-N[S (O) mR x] S (O) m-; Wherein m is selected from 0,1 and 2; And R xBe respectively to be selected from hydrogen and C when each time occurs 1-C 8Alkyl.R aWhen occurring, each time be selected from respectively: (i) hydrogen, halogen atom, cyano group and nitro; (ii) C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, C 2-C 8Alkyl ether, 3 yuan to 10 yuan heterocycles, one-(C 1-C 8Alkyl) amino and two-(C 1-C 8Alkyl) amino and (3 yuan to 10 yuan heterocycles) C 1-C 6Alkyl, it randomly is selected from R respectively by 1 to 9 separately bSubstituent group replace.In some chemical compounds suc as formula I, Ar 2Be 5 yuan to 7 yuan heteroaromatics, randomly replace as described above.
On the other hand, chemical compound provided herein is to be feature with the following formula:
Formula II
Or its pharmaceutically acceptable salt.Among the formula II, U, V, W, X, Y and Z are as previously mentioned.Ar suc as formula II 1And Ar 2Be respectively to be selected from phenyl and 5 yuan and 6 yuan of heteroaromatics separately, it randomly is selected from formula LR respectively by 1 to 3 aThe substituent group of group's (as defined above) replaces.R suc as formula II 7Be C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, one-(C 1-C 8Alkyl) amino or two-(C 1-C 8Alkyl) amino or 3 yuan to 10 yuan heterocycles, it randomly is selected from hydroxyl, halogen atom, C respectively by 1 to 5 separately 1-C 6Alkyl, C 1-C 8Alkoxyl, C 2-C 8Alkyl ether, halo C 1-C 8Alkyl and halo C 1-C 8The substituent group of alkoxyl replaces.
Again on the other hand, chemical compound provided herein is the 2-aminoalkyl-quinazolyl that the is substituted-4-ylamine analogues as formula III:
Figure A0380245200791
Formula III
Or its pharmaceutically acceptable salt or its prodrug, wherein:
V, X, W, Y and Z are as the preamble explanation;
Ar 1And Ar 2Be respectively to be selected from phenyl and 5 yuan to 7 yuan heteroaromatics, it is respectively done for oneself and is unsubstituted or is selected from formula LR as described above respectively by 1 to 3 aSubstituent group replace;
R 3And R 4For:
(i) be selected from respectively separately
(a) hydrogen;
(b) C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, C 1-C 8Alkoxyl, C 3-C 8Alkane ketone, C 2-C 8Alkanoyl, C 2-C 8Alkyl ether, C 6-C 10Aryl C 0-C 8Alkyl, 5 yuan to 10 yuan heterocycle C 0-C 8Alkyl reaches-(SO 2) C 1-C 8Alkyl, it randomly is selected from R respectively by 1 to 9 separately bSubstituent group replace; And
(c) be engaged to R 5Or R 6And forming the group that 4 yuan to 10 a yuan heterocyclic group is rolled into a ball, described heterocyclic group is rolled into a ball to being unsubstituted or being selected from R respectively by 1 to 6 bSubstituent group replace; Or
(ii) be connected to N with its key and engage and form 4 yuan to 10 yuan heterocyclic groups, it is for being unsubstituted or being selected from R respectively by 1 to 6 b, C 1-C 8Alkanoyl, 4 yuan to 7 yuan Heterocyclylalkyl C 0-C 4Alkyl and one-and two-(C 1-C 6Alkyl) amino C 1-C 6The substituent group of alkyl replaces.
R 5And R 6When occurring, each time be respectively:
(i) be selected from respectively separately:
(a) hydrogen or hydroxyl;
(b) C 1-C 8Alkyl, it is for being unsubstituted or being selected from R respectively by 1 to 2 bSubstituent group replace; And
(c) be engaged to R 5Or R 6And forming 4 yuan of groups to 10 yuan of heterocyclic groups, described heterocyclic group is for being unsubstituted or being selected from R respectively by 1 to 6 bSubstituent group replace;
(ii) common in conjunction with and form a ketone group; Or
(iii) engage and form 3 yuan to 7 yuan carbocyclic rings or heterocyclic ring, it is for being unsubstituted or being selected from R by 1 to 4 bSubstituent group replace;
R bBe as the preamble explanation; And
N is 1,2 or 3.
In some others, chemical compound provided herein is the 2-hydroxy alkyl-quinazoline that the is substituted-4-ylamine analogues suc as formula IV:
Formula IV
Or its pharmaceutically acceptable salt or its prodrug, wherein:
V, X, W, Y and Z are as the preamble explanation;
Ar 1And Ar 2Be respectively to be selected from phenyl and 5 yuan to 7 yuan heteroaromatics, it is respectively done for oneself and is unsubstituted or is selected from aforementioned formula such as LR respectively by 1 to 3 aThe substituent group of group replaces;
R 3Be to be selected from:
(a) hydrogen;
(b) C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, C 2-C 8Alkyl ether, C 6-C 10Aryl C 0-C 8Alkyl, and 5 yuan to 10 yuan heterocycle C 0-C 8Alkyl, it randomly is selected from R respectively by 1 to 9 separately bSubstituent group replace; And
(c) be engaged to R 5Or R 6And forming 4 yuan of groups to 10 yuan of heterocyclic groups, described heterocyclic group is for being unsubstituted or being selected from R respectively by 1 to 6 bSubstituent group replace; Or
R 5And R 6When occurring, each time be respectively:
(i) be selected from respectively separately:
(a) hydrogen or hydroxyl;
(b) C 1-C 8Alkyl, it is for being unsubstituted or being selected from R respectively by 1 to 2 bSubstituent group replace; And
(c) be engaged to R 5Or R 6And forming 4 yuan of groups to 10 yuan of heterocyclic groups, described heterocyclic group is for being unsubstituted or being selected from R respectively by 1 to 6 bSubstituent group replace; Or
(ii) engage and form 3 yuan to 7 yuan carbocyclic rings or heterocyclic ring, it is for being unsubstituted or being selected from R by 1 to 4 bSubstituent group replace;
R bBe as the preamble explanation; And
N is 1,2 or 3.
Aspect some, chemical compound described herein has K in the calibrating of capsaicin receptors bind is analyzed iBe not more than 1 μ M, 100nM, 10nM or 1nM, and/or in the calibrating of measuring the capsaicin receptor antagonist activity is analyzed, have IC 50Value is not more than 1 μ M, 100nM, 10nM or 1nM.Preferred chemical compound has generally included higher-strength (promptly low K iOr low IC 50) chemical compound.
Of the present invention some aspect, chemical compound described herein is labelled by detectable marker (for example radioactive label or fluorescein yoke close).
In others, the present invention further provides and comprise at least a chemical compound described herein or salt and acceptable supporting agent of physiology or the bonded medical composition of excipient.
Of the present invention further aspect, the method that reduces the conduction of cell capsaicin receptor calcium is provided, comprise the cell (for example neuronal cell) of expressing the capsaicin receptor and contact with the chemical compound or the salt at least a described herein of effective dose.This kind contact is in vivo or in vitro to test to carry out.
In others, the present invention further provides the inhibition that class vanilloid ligand seat is bonded to the capsaicin receptor.Aspect some, inhibition is to carry out in the test tube test.But this kind method comprises under certain condition and have sufficient amount to suppress class vanilloid ligand seat and capsaicin receptors bind with detection mode, allows the capsaicin receptor contact at least a chemical compound as mentioned above or salt.Aspect this kind, the capsaicin receptor is in patient's body.This kind method comprises the cell that makes at the intravital expression capsaicin of patient receptor and contacts with at least a chemical compound described herein or salt, but its consumption of patient enough suppresses class vanilloid ligand seat with detection mode to be combined with the cell of expression cloning capsaicin receptor in the test tube test, suppresses the capsaicin receptor that class vanilloid ligand seat is bonded to patient's body thus.
The present invention provides the treatment of diseases method to responding property of capsaicin receptor adjusting to the patient in others, comprises to give chemical compound at least a described herein or the salt that the capsaicin receptor is regulated effective dose to the patient, relaxes patient's the state of an illness thus.
In others, be provided as the method for patient treatment pain, comprise suffering from chemical compound at least a described herein or the salt that pain patients gives capsaicin receptor adjusting consumption, alleviate patient's pain thus.
In others, be provided as further that patient treatment is scratched where it itches, urinary incontinence, the method for coughing and/or having the hiccups, comprise the chemical compound at least a described herein or the salt that the patient who suffers from aforementioned one or more state of an illness are given capsaicin receptor adjusting consumption, alleviate conditions of patients thus.
The present invention further provides the method that promotes that the obese patient loses weight, comprise at least a chemical compound as described here or the salt that the obese patient are given capsaicin receptor regulated quantity, promote losing weight of patient thus.
In others, the invention provides the method that whether has the capsaicin receptor in the working sample, comprise the following step: sample and chemical compound described herein are contacted under the condition of this chemical compound in conjunction with the capsaicin receptor allowing, and (b) detection compound is bonded to the degree of capsaicin receptor.
The present invention further provides the packing pharmaceutical preparation, comprise: (a) a kind of medical composition as described here in a container; And (b) use said composition to treat one or more capsaicin receptor regulated the indication of the disease that responds, these diseases for example for pain, scratch where it itches, urinary incontinence, cough, have the hiccups and/or fat.
Again on the other hand, the invention provides the method for preparation chemical compound disclosed herein, comprise intermedium.
These and other aspect of the present invention is also with reference to hereinafter describing in detail with more clear and definite.
Embodiment
As the preamble explanation, the invention provides the capsaicin receptor modulators that comprises the quinazoline-4-ylamine analogues that is substituted.This kind regulator can make the capsaicin receptor active that is used for regulating (the preferred inhibition) each side in external or body.
Some chemical compounds suc as formula I comprise following chemical compound, wherein:
V, X, W, Y and Z are respectively N or CR separately 1, condition is that among V and the X at least one is for N;
U is N or CR 2, but if V and X are N, then U is CR 2
R 1Be respectively to be selected from hydrogen, halogen atom, hydroxyl, amino, C when each time occurs 1-C 8Alkyl, halo C 1-C 8Alkyl, C 1-C 8Alkoxyl, halo C 1-C 8Alkoxyl and one-(C 1-C 8Alkyl) amino and two-(C 1-C 8Alkyl) amino;
R 2For: (i) hydrogen, halogen atom, cyano group or-COOH;
(ii) C 1-C 8Alkanoyl, C 2-C 8Alkane ketone or C 1-C 8The carbamic acid root, it is respectively done for oneself and is unsubstituted or is selected from R respectively by 1 to 9 bSubstituent group replace; Or
(iii) suc as formula-R c-M-A-R yGroup, wherein:
R cBe C 0-C 3Alkyl;
M is that key connects, N (R z), O, S, SO 2, C (=O) pN (R z), N (R z) C (=O) p, SO 2N (R z) or N (R z) SO 2, wherein p is 0 or 1;
A is that key connects or C 1-C 8Alkyl randomly is selected from R respectively by 1 to 3 bSubstituent group replace; And
R yAnd R zIf when existing be:
(a) be respectively hydrogen, C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, C 6-C 10Aryl C 1-C 8Alkyl, C 2-C 8Alkyl ether, C 1-C 8Alkoxyl, 4 yuan to 10 yuan carbocyclic rings or heterocycle, or R yAnd R zBe engaged to R cAnd form 4 yuan to 10 yuan carbocyclic rings or heterocycle, wherein each R yAnd R zBe respectively and be unsubstituted or be selected from R respectively by 1 to 9 bSubstituent group replace; Or
(b) engage and form 4 yuan to 10 yuan carbocyclic rings or heterocycle, it is for being unsubstituted or being selected from R respectively by 1 to 9 bSubstituent group replace.
Ar 2Be 5 yuan to 7 yuan heteroaromatics, randomly be selected from formula LR respectively by 1 to 3 aThe substituent group of group replace;
Ar 1Be 5 yuan to 10 yuan aromatic carbon rings or heterocycle, randomly be selected from formula LR respectively by 1 to 3 aThe substituent group of group replace;
L when each time occurs be respectively be selected from key connect ,-O-,-C (=O)-,-OC (=O)-,-C (=O) O-,-O-C (=O) O-,-S (O) m-,-NR x-,-C (=O) NHR x-,-NHR xC (=O)-,-NR xS (O) m-, S (O) mNR x-and-N[S (O) mR x] S (O) m-; Wherein m is selected from 0,1 and 2; And R xBe respectively to be selected from hydrogen and C when each time occurs 1-C 8Alkyl.
R aWhen occurring, each time be selected from respectively:
(i) hydrogen, halogen atom, cyano group and nitro; And
(ii) C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, C 2-C 8Alkyl ether, 3 yuan to 10 yuan heterocycles, one-(C 1-C 8Alkyl) amino and two-(C 1-C 8Alkyl) amino and (3 yuan to 10 yuan heterocycles) C 1-C 6Alkyl, it is respectively done for oneself and is unsubstituted or is selected from R respectively by 1 to 9 bSubstituent group replace; And
R bBe respectively to be selected from hydroxyl, halogen atom, amino, amino carbonyl, acylamino-, cyano group, nitro, ketone group, C when each time occurs 1-C 8Alkyl, C 1-C 8Alkoxyl, C 1-C 8Alkylthio group, C 1-C 8Alkyl ether, hydroxyl C 1-C 8Alkyl, halogen C 1-C 8Alkyl, phenyl, phenyl (C 1-C 8Alkyl), one-(C 1-C 6Alkyl) amino and two-(C 1-C 6Alkyl) amino, (SO 2) C 1-C 8Alkyl, 5 yuan to 7 yuan heterocycles reach (5 yuan to 7 yuan heterocycles) (C 1-C 8Alkyl).
These chemical compounds are referred to as formula Ib chemical compound herein.
In some formula Ib chemical compounds, Ar 2Be to be selected from pyridine radicals, pyridazinyl, pyrimidine radicals, piperazine pyrazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl and thiadiazolyl group, it is respectively done for oneself and is unsubstituted or is selected from halogen atom, cyano group, C by 1 or 2 1-C 6Alkyl, halo C 1-C 6Alkyl, hydroxyl C 1-C 6Alkyl, C 1-C 6Alkyl ether, C 1-C 6Alkanoyl, amino, one-(C 1-C 6Alkyl) amino and two-(C 1-C 6Alkyl) amino substituent group replaces.In some specific embodiment, Ar 2Be pyridine radicals, isoxazolyl, thiadiazolyl group or pyrazolyl, it is respectively done for oneself and is unsubstituted or by halogen atom, C 1-C 4Alkyl or halo C 1-C 4Alkyl replaces.
In some specific embodiment, Ar 1Be phenyl or pyridine radicals, randomly by halogen atom, C 1-C 6Alkyl, halo C 1-C 6Alkyl, C 1-C 6Alkoxyl or halo C 1-C 6Alkoxyl replaces.
In some chemical compounds suc as formula Ib, U is CR 2In some specific embodiment, R 2For:
(i) hydrogen or halogen atom; Or
(ii) C 1-C 6Alkyl ,-(CH 2) nNH ,-(CH 2) nNH (C 1-C 8Alkyl) ,-(CH 2) nN (C 1-C 8Alkyl) 2,-(CH 2) n(5 yuan to 8 yuan Heterocyclylalkyls) ,-(CH 2) nOH or-(CH 2) nO (C 1-C 8Alkyl), it is respectively done for oneself and is unsubstituted or is selected from halogen atom, cyano group, hydroxyl, amino, one-(C respectively by 1 to 4 1-C 6Alkyl) amino and two-(C 1-C 6Alkyl) amino, C 1-C 6Alkyl and halo C 1-C 6The substituent group of alkyl replaces.
On the other hand, the invention provides chemical compound suc as formula Iib, that is formula II chemical compound, wherein
V, X, W, Y and Z are respectively N or CR separately 1, condition is that among V and the X at least one is for N;
U is N or CR 2, but if V and X are N, then U is CR 2
R 1Be respectively to be selected from hydrogen, halogen atom, hydroxyl, amino, C when each time occurs 1-C 8Alkyl, halo C 1-C 8Alkyl, C 1-C 8Alkoxyl, halo C 1-C 8Alkoxyl and one-(C 1-C 8Alkyl) amino and two-(C 1-C 8Alkyl) amino;
R 2For: (i) hydrogen, halogen atom, cyano group or-COOH;
(ii) C 1-C 8Alkanoyl, C 2-C 8Alkane ketone or C 1-C 8The carbamic acid root, it is respectively done for oneself and is unsubstituted or is selected from R respectively by 1 to 9 bSubstituent group replace; Or
(iii) suc as formula-R c-M-A-R yGroup, wherein:
R cBe C 0-C 3Alkyl;
M is that key connects, N (R z), O, S, SO 2, C (=O) pN (R z), N (R z) C (=O) p, SO 2N (R z) or N (R z) SO 2, wherein p is 0 or 1;
A is that key connects or C 1-C 8Alkyl randomly is selected from R respectively by 1 to 3 bSubstituent group replace; And
R yAnd R zIf when existing be:
(a) be respectively hydrogen, C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, C 6-C 10Aryl C 1-C 8Alkyl, C 2-C 8Alkyl ether, C 1-C 8Alkoxyl, 4 yuan to 10 yuan carbocyclic rings or heterocycle, or R yAnd R zBe engaged to R cAnd form 4 yuan to 10 yuan carbocyclic rings or heterocycle, wherein each R yAnd R zBe respectively and be unsubstituted or be selected from R respectively by 1 to 9 bSubstituent group replace; Or
(b) engage and form 4 yuan to 10 yuan carbocyclic rings or heterocycle, it is for being unsubstituted or being selected from R respectively by 1 to 9 bSubstituent group replace.
Ar 1And Ar 2Be respectively to be selected from phenyl and 5 yuan and 6 yuan of heteroaromatics, it randomly is selected from formula LR respectively by 1 to 3 aThe substituent group of group replaces;
L when occurring separately be respectively be selected from key connect ,-O-,-C (=O)-,-OC (=O)-,-C (=O) O-,-O-C (=O) O-,-S (O) m-,-NR x-,-C (=O) NHR x-,-NHR xC (=O)-,-NR xS (O) m-, S (O) mNR x-and-N[S (O) mR x] S (O) m-; Wherein m is selected from 0,1 and 2; And R xBe respectively to be selected from hydrogen and C when each time occurs 1-C 8Alkyl.
R aWhen occurring, each time be selected from respectively:
(i) hydrogen, halogen atom, cyano group and nitro; And
(ii) C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, C 2-C 8Alkyl ether, 3 yuan to 10 yuan heterocycles, one-(C 1-C 8Alkyl) amino and two-(C 1-C 8Alkyl) amino and (3 yuan to 10 yuan heterocycles) C 1-C 6Alkyl, it is respectively done for oneself and is unsubstituted or is selected from R respectively by 1 to 9 bSubstituent group replace;
R bBe respectively to be selected from hydroxyl, halogen atom, amino, amino carbonyl, acylamino-, cyano group, nitro, ketone group, C when each time occurs 1-C 8Alkyl, C 1-C 8Alkoxyl, C 1-C 8Alkylthio group, C 1-C 8Alkyl ether, hydroxyl C 1-C 8Alkyl, halogen C 1-C 8Alkyl, phenyl, phenyl (C 1-C 8Alkyl), one-(C 1-C 6Alkyl) amino and two-(C 1-C 6Alkyl) amino, (SO 2) C 1-C 8Alkyl, 5 yuan to 7 yuan heterocycles reach (5 yuan to 7 yuan heterocycles) (C 1-C 8Alkyl); And
R 7Be C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, one-(C 1-C 8Alkyl) amino or two-(C 1-C 8Alkyl) amino or 3 yuan to 10 yuan heterocycles, it randomly is selected from hydroxyl, halogen atom, C respectively by 1 to 5 separately 1-C 6Alkyl, C 1-C 8Alkoxyl, C 2-C 8Alkyl ether, halo C 1-C 8Alkyl and halo C 1-C 8The substituent group of alkoxyl replaces.
In some chemical compounds suc as formula IIb, Ar 2Be phenyl or pyridine radicals, it randomly is selected from halogen atom, cyano group, C by 1 or 2 separately 1-C 6Alkyl and halo C 1-C 6The substituent group of alkyl replaces.In some chemical compounds, Ar 2Be phenyl, randomly by halogen atom, C 1-C 4Alkyl or halo C 1-C 4Alkyl replaces.
In some chemical compounds suc as formula IIb, Ar 1Be phenyl or pyridine radicals, randomly by halogen atom, C 1-C 6Alkyl, halo C 1-C 6Alkyl, C 1-C 6Alkoxyl or halo C 1-C 6Alkoxyl replaces.In some specific embodiment embodiments, Ar 1And Ar 2The pyridine radicals of respectively doing for oneself is selected from halogen atom, C respectively by one 1-C 4Alkyl, C 1-C 4Haloalkyl and C 1-C 4The substituent group of alkoxyl replaces.
In some chemical compounds suc as formula IIb, U is CR 2In some specific embodiment, R 2For:
(i) hydrogen or halogen atom; Or
(ii) C 1-C 6Alkyl ,-(CH 2) nNH ,-(CH 2) nNH (C 1-C 8Alkyl) ,-(CH 2) nN (C 1-C 8Alkyl) 2,-(CH 2) n(5 yuan to 8 yuan Heterocyclylalkyls) ,-(CH 2) nOH or-(CH 2) nO (C 1-C 8Alkyl), it is respectively done for oneself and is unsubstituted or is selected from halogen atom, cyano group, hydroxyl, amino, one-(C respectively by 1 to 4 1-C 6Alkyl) amino and two-(C 1-C 6Alkyl) amino, C 1-C 6Alkyl and halo C 1-C 6The substituent group of alkyl replaces.In some specific embodiment, X and the V N that respectively does for oneself.
In some chemical compounds suc as formula IIb, R 7Comprise direct key and be connected to SO 2Nitrogen-atoms.In some specific embodiment, R 7Be amino, one-(C 1-C 6Alkyl) amino or two-(C 1-C 6Alkyl) amino, morpholinyl, piperidyl, piperazinyl or Pyrrolizidine base, it is respectively done for oneself and is unsubstituted or is selected from halogen atom, C respectively by 1 to 3 1-C 6Alkyl and halo C 1-C 6The substituent group of alkyl replaces.In other formula IIb chemical compound, R 7Be C 1-C 6Alkyl, halo C 1-C 6Alkyl, morpholinyl, piperidyl, piperazinyl or Pyrrolizidine base, it randomly is selected from C respectively by 1 to 5 1-C 6Alkyl, C 1-C 6Alkoxyl, C 1-C 6Alkyl ether, halo C 1-C 6Alkyl and halo C 1-C 6The substituent group of alkoxyl replaces.
On the other hand, the invention provides the chemical compound suc as formula IIIb, that is chemical compound wherein: V, X, W, Y and Z are respectively N or CR separately 1, condition is that among V and the X at least one is for N;
R 1Be respectively to be selected from hydrogen, halogen atom, hydroxyl, cyano group, amino, C when each time occurs 1-C 8Alkyl, halo C 1-C 8Alkyl, C 1-C 8Alkoxyl, halo C 1-C 8Alkoxyl and one-(C 1-C 6Alkyl) amino and two-(C 1-C 6Alkyl) amino;
Ar 1And Ar 2Be respectively to be selected from phenyl and 5 yuan to 7 yuan heteroaromatics, it is respectively done for oneself and is unsubstituted or is selected from formula LR respectively by 1 to 3 aThe substituent group of group replaces;
L when occurring separately be respectively be selected from key connect ,-O-,-C (=O)-,-OC (=O)-,-C (=O) O-,-O-C (=O) O-,-S (O) m-,-NR x-,-C (=O) NHR x-,-NHR xC (=O)-,-NR xS (O) m-, S (O) mNR x-and-N[S (O) mR x] S (O) m-; Wherein m is selected from 0,1 and 2; And R xBe respectively to be selected from hydrogen and C when each time occurs 1-C 8Alkyl;
R aWhen occurring, each time be selected from respectively:
(i) hydrogen, halogen atom, cyano group and nitro; And
(ii) C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, C 2-C 8Alkyl ether, 3 yuan to 10 yuan heterocycles, and (3 yuan to 10 yuan heterocycles) C 1-C 6Alkyl, it is respectively done for oneself and is unsubstituted or is selected from R respectively by 1 to 9 bSubstituent group replace;
R 3And R 4For:
(i) be selected from respectively separately
(a) hydrogen;
(b) C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, C 1-C 8Alkoxyl, C 3-C 8Alkane ketone, C 2-C 8Alkanoyl, C 2-C 8Alkyl ether, C 6-C 10Aryl C 0-C 8Alkyl, 5 yuan to 10 yuan heterocycle C 0-C 8Alkyl reaches-(SO 2) C 1-C 8Alkyl, it randomly is selected from R respectively by 1 to 9 separately bSubstituent group replace; And
(c) be engaged to R 5Or R 6And forming the group that 4 yuan to 10 a yuan heterocyclic group is rolled into a ball, described heterocyclic group is for being unsubstituted or being selected from R respectively by 1 to 6 bSubstituent group replace; Or
(ii) be connected to N on it with key and engage and form 4 yuan to 10 a yuan heterocycle families ring, it is for being unsubstituted or being selected from R respectively by 1 to 6 b, C 1-C 8Alkanoyl, 4 yuan to 7 yuan Heterocyclylalkyl C 0-C 4Alkyl, and one-and two-(C 1-C 6Alkyl) amino C 1-C 6The substituent group of alkyl replaces.
R 5And R 6When occurring, each time be respectively:
(i) be selected from respectively separately:
(a) hydrogen or hydroxyl;
(b) C 1-C 8Alkyl, it is for being unsubstituted or being selected from R respectively by 1 to 2 bSubstituent group replace; And
(c) be engaged to R 5Or R 6And forming 4 yuan of groups to 10 yuan of heterocyclic groups, described heterocyclic aryl is for being unsubstituted or being selected from R respectively by 1 to 6 bSubstituent group replace;
(ii) common in conjunction with and form a ketone group; Or
(iii) engage and form 3 yuan to 7 yuan carbocyclic rings or heterocyclic ring, it is for being unsubstituted or being selected from R by 1 to 4 bSubstituent group replace;
R bBe respectively to be selected from hydroxyl, halogen atom, amino, amino carbonyl, acylamino-, cyano group, nitro, ketone group, C when each time occurs 1-C 8Alkyl, C 1-C 8Alkoxyl, C 1-C 8Alkylthio group, C 1-C 8Alkyl ether, hydroxyl C 1-C 8Alkyl, halogen C 1-C 8Alkyl, phenyl, phenyl (C 1-C 8Alkyl), one-(C 1-C 6Alkyl) amino and two-(C 1-C 6Alkyl) amino, (SO 2) C 1-C 8Alkyl, 5 yuan to 7 yuan heterocycles reach (5 yuan to 7 yuan heterocycles) (C 1-C 8Alkyl); And
N is 1,2 or 3.
In some chemical compounds suc as formula IIIb, Ar 1And Ar 2Be respectively to be selected from phenyl and 6 yuan of heteroaromatics, it is replaced by 0,1 or 2 substituent group separately.In some specific embodiment, (i) Ar 1Be phenyl or pyridine radicals, it is respectively done for oneself and is unsubstituted or is selected from halogen atom, hydroxyl, cyano group, amino, nitro ,-(C by 1 or 2 1-C 6Alkyl) amino and two-(C 1-C 6Alkyl) amino, C 1-C 6Alkyl, halo C 1-C 6Alkyl, C 1-C 6Alkoxyl and halo C 1-C 6The substituent group of alkoxyl replaces; And (ii) Ar 2Be phenyl or pyridine radicals, it is respectively done for oneself and is unsubstituted or is selected from halogen atom, hydroxyl, cyano group, amino, one-(C respectively by 1 or 2 1-C 6Alkyl) amino and two-(C 1-C 6Alkyl) amino, C 1-C 6Alkyl, halo C 1-C 6Alkyl, C 1-C 6Alkoxyl, halo C 1-C 6Alkoxyl, C 2-C 6Alkyl ether, C 1-C 6Alkanoyl ,-(SO 2) R 2,-NR xS (O) m-and-N (S (O m) 2Substituent group replace; Wherein m is 1 or 2, R xBe hydrogen or C 1-C 6Alkyl and R 2Be C 1-C 6Alkyl, halo C 1-C 6Alkyl, amino, one-or two-(C 1-C 6Alkyl) amino or 5 yuan to 10 yuan N binding heterocyclic radicals, each R 2Randomly by R bReplace.For example, in some specific embodiment, (i) Ar 1Be pyridine radicals, it is for being unsubstituted or by halogen atom, C 1-C 4Alkyl or halo C 1-C 4Alkyl replaces; And (ii) Ar 2Be phenyl or pyridine radicals, it is respectively done for oneself and is unsubstituted or by halogen atom, cyano group, C 1-C 4Alkyl, halo C 1-C 4Alkyl, C 2-C 4Alkyl ether, C 1-C 4Alkanoyl or-(SO 2) R aReplace, wherein R aBe C 1-C 4Alkyl or halo C 1-C 4Alkyl.Some chemical compounds are (i) Ar wherein 1Be pyridine-2-base, 3-methyl-pyridine-2-base, 3-trifluoromethyl-pyridine-2-base or 3-halogen-pyridine-2-base; And (ii) Ar 2Be phenyl, 2-pyridine radicals or 3-pyridine radicals, its each comfortable 4 positions are by trifluoromethane sulfonyl group, propane sulfonyl, propane-2-sulfonyl, the tert-butyl group, trifluoromethyl or 2,2, and 2-three fluoro-1-methyl-ethyl replaces.
In some chemical compounds suc as formula IIIb, R 3And R 4Be respectively separately: (i) hydrogen; Or (ii) C 1-C 8Alkyl, C 2-C 8Thiazolinyl, phenyl C 0-C 4Alkyl, 2,3 indanyl C 0-C 4Alkyl, 5 yuan to 6 yuan heteroaryl C 0-C 4Alkyl or 4 yuan to 7 yuan Heterocyclylalkyl C 0-C 4Alkyl, it is respectively done for oneself and is unsubstituted or is selected from hydroxyl, halogen atom, amino, C respectively by 1 to 4 1-C 6Alkyl, halo C 1-C 6Alkyl, C 1-C 6Alkoxyl and halo C 1-C 6The substituent group of alkoxyl replaces.In some specific embodiment, R 3And R 4Be respectively (i) hydrogen separately; Or (ii) C 1-C 6Alkyl, C 2-C 6Thiazolinyl, 5 yuan to 7 yuan heterocycle C 0-C 4Alkyl, C 2-C 6Alkyl ether, 2,3 indanyls, benzyl, 1-phenethyl, 1-phenylpropyl and 2-phenethyl, it is respectively done for oneself and is unsubstituted or is selected from hydroxyl, halogen atom and C respectively by 1 to 3 1-C 4The substituent group of alkyl replaces.R for example 3And R 4One be pyridine radicals C 0-C 4Alkyl, pyrimidine radicals C 0-C 4Alkyl, imidazole radicals C 0-C 4Alkyl or tetrazole radical C 0-C 4Alkyl, it is replaced by 0,1 or 2 substituent group separately.
In some chemical compounds suc as formula IIIb, R 3With R 4Engage and form 5 yuan to 10 yuan heterocyclic groups, it is replaced by 0 to 4 substituent group.In some specific embodiment, heterocyclic group is selected from hydroxyl, halogen atom, C by at least one 1-C 4Alkyl, halo C 1-C 4Alkyl, C 1-C 4Alkoxyl, halo C 1-C 4Alkoxyl, C 1-C 4Alkanoyl and aminocarboxy substituent group replace.In some specific embodiment, heterocyclic group comprises aromatic rings.A heterocyclic group is by 3 of 0,1 or 2 substituent group replacement, 4-dihydro-1H-isoquinolin-2-base.In other specific embodiment, heterocyclic group is 5 yuan to 10 yuan Heterocyclylalkyls, and it is replaced by 0 to 4 substituent group.For example Heterocyclylalkyl is the hot cyclic group of piperidyl, piperazinyl, Pyrrolizidine base, a nitrogen cyclic group in heptan, a nitrogen, decahydroquinolyl or 1, and in 4-two Evil-8-a word used for translation-spiral shell [4.5] last of the ten Heavenly stems-8-base, it is respectively done for oneself and is unsubstituted or is selected from halogen atom, hydroxyl, C respectively by 1 to 4 1-C 4Alkyl, C 1-C 4Alkoxyl, halo C 1-C 4Alkyl, halo C 1-C 4Alkoxyl, C 1-C 4Alkanoyl and C 1-C 4The substituent group of alkoxy carbonyl group replaces.Heterocyclic group comprises morpholinyl, tetrahydro-1,4-thiazine base or 1 in addition, 1-diketo-tetrahydro-1,4-thiazine-4-base, and it is respectively done for oneself and is unsubstituted or is selected from halogen atom, hydroxyl, C respectively by 1 to 4 1-C 4Alkyl, C 1-C 4Alkoxyl, halo C 1-C 4Alkyl, halo C 1-C 4Alkoxyl, C 1-C 4Alkanoyl and C 1-C 4The substituent group of alkoxy carbonyl group replaces.In some chemical compounds, heterocyclic group is replaced by 1 to 4 substituent group that is selected from methyl and ethyl respectively.
In some chemical compounds suc as formula IIIb, R 5And R 6Be selected from hydrogen and C separately respectively 1-C 6Alkyl.In some specific embodiment, R 5And R 6Be hydrogen.
In some chemical compounds suc as formula IIIb, n is 1.
Some representational chemical compounds suc as formula IIIb are following chemical compound, wherein:
(i) V and X are N;
(ii) Ar 1Be pyridine radicals, it is for being unsubstituted or by halogen atom, C 1-C 4Alkyl or halo C 1-C 4Alkyl replaces;
(iii) Ar 2Be phenyl or pyridine radicals, it is for being unsubstituted or by C 1-C 4Alkyl, halo C 1-C 4Alkyl or formula-(SO 2) R 2Group replaces, wherein R 2Be C 1-C 4Alkyl or halo C 1-C 4Alkyl;
(iv) R 3And R 4Be respectively to be selected from C separately 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkyl ether, 5 yuan to 10 yuan heteroaryl C 0-C 4Alkyl, phenyl C 0-C 4Alkyl and 2,3 indanyls, it is selected from hydroxyl, halogen atom, C respectively by 0,1 or 2 separately 1-C 4Alkyl and halo C 1-C 4The substituent group of alkyl replaces; And
(v) n is 1.
It is following chemical compound that other chemical compound suc as formula IIIb is arranged again, wherein:
(i) V and X are N;
(ii) Ar 1Be pyridine radicals, it is for being unsubstituted or by halogen atom, C 1-C 4Alkyl or halo C 1-C 4Alkyl replaces;
(iii) Ar 2Be phenyl or pyridine radicals, it is for being unsubstituted or by C 1-C 4Alkyl, halo C 1-C 4Alkyl or formula-(SO 2) R 2Group replaces, wherein R 2Be C 1-C 4Alkyl or halo C 1-C 4Alkyl;
(iv) R 3And R 4Engage and form 5 yuan to 10 yuan heterocyclic groups, it is for being unsubstituted or by 1 to 3 substituent group replacement; And
(v) n is 1.
Again on the other hand, the invention provides chemical compound suc as formula IVb, that is in the formula IV chemical compound:
V, X, W, Y and Z are respectively N or CR separately 1, but among V and the X at least one is N;
R 1Be respectively to be selected from hydrogen, halogen atom, hydroxyl, cyano group, amino, C when each time occurs 1-C 8Alkyl, halo C 1-C 8Alkyl, C 1-C 8Alkoxyl, halo C 1-C 8Alkoxyl and one-(C 1-C 6Alkyl) amino and two-(C 1-C 6Alkyl) amino;
Ar 1And Ar 2Be respectively to be selected from phenyl and 5 yuan to 7 yuan heteroaromatics, it is respectively done for oneself and is unsubstituted or is selected from formula LR respectively by 1 to 3 aThe substituent group of group replaces;
L when occurring separately be respectively be selected from key connect ,-O-,-C (=O)-,-OC (=O)-,-C (=O) O-,-O-C (=O) O-,-S (O) m-,-NR x-,-C (=O) NHR x-,-NHR xC (=O)-,-NR xS (O) m-, S (O) mNR x-and-N[S (O) mR x] S (O) m-; Wherein m is selected from 0,1 and 2; And R xBe respectively to be selected from hydrogen and C when each time occurs 1-C 8Alkyl;
R aWhen occurring, each time be selected from respectively:
(i) hydrogen, halogen atom, cyano group and nitro; And
(ii) C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, C 2-C 8Alkyl ether, 3 yuan to 10 yuan heterocycles ,-and two-(C 1-C 8Alkyl) amino and (3 yuan to 10 yuan heterocycles) C 1-C 6Alkyl, it is respectively done for oneself and is unsubstituted or is selected from R respectively by 1 to 9 bSubstituent group replace;
R 3Be to be selected from:
(i) hydrogen;
(ii) C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, C 3-C 8Alkane ketone, C 2-C 8Alkyl ether, C 6-C 10Aryl C 0-C 8Alkyl and 5 yuan to 10 yuan heterocycle C 0-C 8Alkyl, it randomly is selected from R respectively by 1 to 9 separately bSubstituent group replace; And
(iii) be engaged to R 5Or R 6And forming 4 yuan of groups to 10 yuan of heterocyclic groups, described heterocyclic group is for being unsubstituted or being selected from R respectively by 1 to 6 bSubstituent group replace;
R 5And R 6When occurring, each time be respectively:
(i) be selected from respectively separately:
(a) hydrogen or hydroxyl;
(b) C 1-C 8Alkyl, it is for being unsubstituted or being selected from R respectively by 1 to 2 bSubstituent group replace; And
(c) be engaged to R 3And forming 4 yuan of groups to 10 yuan of heterocyclic groups, described heterocyclic group is for being unsubstituted or being selected from R respectively by 1 to 6 bSubstituent group replace; Or
(ii) engage and form 3 yuan to 7 yuan carbocyclic rings or heterocyclic ring, it is for being unsubstituted or being selected from R by 1 to 4 bSubstituent group replace;
R bBe respectively to be selected from hydroxyl, halogen atom, amino, amino carbonyl, acylamino-, cyano group, nitro, ketone group, C when each time occurs 1-C 8Alkyl, C 1-C 8Alkoxyl, C 1-C 8Alkylthio group, C 1-C 8Alkyl ether, hydroxyl C 1-C 8Alkyl, halogen C 1-C 8Alkyl, phenyl, phenyl (C 1-C 8Alkyl), one-(C 1-C 6Alkyl) amino and two-(C 1-C 6Alkyl) amino, (SO 2) C 1-C 8Alkyl, 5 yuan to 7 yuan heterocycles reach (5 yuan to 7 yuan heterocycles) (C 1-C 8Alkyl); And
N is 1,2 or 3.
In some chemical compounds suc as formula IVb, Ar 1And Ar 2Be respectively to be selected from phenyl and 6 yuan of heteroaromatics, it is replaced by 0,1 or 2 substituent group separately.In some specific embodiment, (i) Ar 1Be phenyl or pyridine radicals, it is respectively done for oneself and is unsubstituted or is selected from halogen atom, hydroxyl, cyano group, amino, nitro ,-(C by 1 or 2 1-C 6Alkyl) amino and two-(C 1-C 6Alkyl) amino, C 1-C 6Alkyl, halo C 1-C 6Alkyl, C 1-C 6Alkoxyl and halo C 1-C 6The substituent group of alkoxyl replaces; And (ii) Ar 2Be phenyl or pyridine radicals, it is respectively done for oneself and is unsubstituted or is selected from halogen atom, hydroxyl, cyano group, amino, nitro ,-(C by 1 or 2 1-C 6Alkyl) amino and two-(C 1-C 6Alkyl) amino, C 1-C 6Alkyl, halo C 1-C 6Alkyl, C 1-C 6Alkoxyl, halo C 1-C 6Alkoxyl, C 2-C 6Alkyl ether, C 1-C 6Alkanoyl ,-(SO 2) R 2,-NR xS (O) m-and-N (S (O m) 2Substituent group replace; Wherein m is 1 or 2, R xBe hydrogen or C 1-C 6Alkyl and R 2Be C 1-C 6Alkyl, halo C 1-C 6Alkyl, amino, one-or two-(C 1-C 6Alkyl) amino or 5 yuan to 10 yuan N binding heterocyclic radicals, each R 2Randomly by R bReplace.In some specific embodiment, (i) Ar 1Be pyridine radicals, it is for being unsubstituted or by halogen atom, C 1-C 4Alkyl or halo C 1-C 4Alkyl replaces; And (ii) Ar 2Be phenyl or pyridine radicals, it is for being unsubstituted or by C 1-C 4Alkyl, halo C 1-C 4Alkyl or-(SO 2) R 2Group (R wherein 2Be C 1-C 4Alkyl or halo C 1-C 4Alkyl) replaces.(i) Ar in some chemical compounds 1Be pyridine-2-base, 3-methyl-pyridine-2-base, 3-trifluoromethyl-pyridine-2-base or 3-halogen-pyridine-2-base; And (ii) Ar 2Be phenyl, 2-pyridine radicals or 3-pyridine radicals, its each comfortable 4 positions are by trifluoromethane sulfonyl group, propane sulfonyl, propane-2-sulfonyl, the tert-butyl group, trifluoromethyl or 2,2, and 2-three fluoro-1-methyl-ethyl replaces.
In some chemical compounds suc as formula IVb, R 3For: (i) hydrogen; Or (ii) C 1-C 8Alkyl, C 2-C 8Thiazolinyl, phenyl C 0-C 4Alkyl, 5 yuan to 6 yuan heteroaryl C 0-C 4Alkyl or 4 yuan to 7 yuan Heterocyclylalkyl C 0-C 4Alkyl, it is respectively done for oneself and is unsubstituted or is selected from hydroxyl, halogen atom, amino, C respectively by 1 to 4 1-C 6Alkyl, halo C 1-C 6Alkyl, C 1-C 6Alkoxyl and halo C 1-C 6The substituent group of alkoxyl replaces.In some specific embodiment, R 3Be (i) hydrogen; Or (ii) C 1-C 6Alkyl or benzyl, it is respectively done for oneself and is unsubstituted or is selected from hydroxyl, halogen atom and C respectively by 1 to 3 1-C 4The substituent group of alkyl replaces.
In some chemical compounds suc as formula IVb, R 5And R 6Be respectively to be selected from hydrogen and C separately 1-C 6Alkyl.In some specific embodiment, R 5And R 6Be hydrogen.
In some chemical compounds suc as formula IVb, n is 1.
Some representational chemical compounds suc as formula IVb are following chemical compound, wherein:
(i) V and X are N;
(ii) Ar 1Be pyridine radicals, it is for being unsubstituted or by halogen atom, C 1-C 4Alkyl or halo C 1-C 4Alkyl replaces;
(iii) Ar 2Be phenyl or pyridine radicals, it is for being unsubstituted or by C 1-C 4Alkyl, halo C 1-C 4Alkyl or formula-(SO 2) R 2Group replaces, wherein R 2Be C 1-C 4Alkyl or halo C 1-C 4Alkyl;
(iv) R 3Be to be selected from (a) hydrogen; And (b) C 1-C 6Alkyl, C 2-C 6Thiazolinyl and phenyl C 0-C 4Alkyl, it is selected from hydroxyl, halogen atom, C respectively by 0,1 or 2 separately 1-C 4Alkyl and halo C 1-C 4The substituent group of alkyl replaces; And
(v) n is 1.
Preferably the chemical compound suc as formula Ib, IIb, IIIb and IVb has IC in the calibrating of capsaicin receptor calcium mobility is analyzed 50Be value 100nM or following, 10nM or following or 1nM or following.
On the other hand, the invention provides medical composition, comprise at least a chemical compound or salt, combine with a kind of physiologically acceptable supporting agent or excipient according to formula Ib, IIb, IIIb and IVb.
In the described herein the whole bag of tricks, the VR1 regulator of use can satisfy one or many formulas: I, II, III, IV, Ia, IIa, IIIa, IVa, Ib, IIb, IIIb or IVb of following formula.Some regulators can satisfy formula I, wherein
V, X, W, Y and Z are respectively N or CR separately 1, condition is that among V and the X at least one is for N;
U is N or CR 2, but if V and X are N, then U is CR 2
R 1Be respectively to be selected from hydrogen, halogen atom, hydroxyl, cyano group, amino, C when each time occurs 1-C 8Alkyl, halo C 1-C 8Alkyl, C 1-C 8Alkoxyl, halo C 1-C 8Alkoxyl and one-(C 1-C 8Alkyl) amino and two-(C 1-C 8Alkyl) amino;
R 2For: (i) hydrogen, halogen atom, cyano group or-COOH;
(ii) C 1-C 8Alkanoyl, C 2-C 8Alkane ketone or C 1-C 8The carbamic acid root, it is respectively done for oneself and is unsubstituted or is selected from R respectively by 1 to 9 bSubstituent group replace; Or
(iii) suc as formula-R c-M-A-R yGroup, wherein:
R cBe C 0-C 3Alkyl;
M is that key connects N (R z), O, S, SO 2, C (=O) pN (R z), N (R z) C (=O) p, SO 2N (R z) or N (R z) SO 2, wherein p is 0 or 1;
A is that key connects or C 1-C 8Alkyl randomly is selected from R respectively by 1 to 3 bSubstituent group replace; And
R yAnd R zFor:
(a) be respectively hydrogen, C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, C 6-C 10Aryl C 1-C 8Alkyl, C 2-C 8Alkyl ether, C 1-C 8Alkoxyl, 4 yuan to 10 yuan carbocyclic rings or heterocycle, or R yAnd R zBe engaged to R cAnd form 4 yuan to 10 yuan carbocyclic rings or heterocycle, wherein each R yAnd R zBe respectively and be unsubstituted or be selected from R respectively by 1 to 9 bSubstituent group replace; Or
(b) engage and form 4 yuan to 10 yuan carbocyclic rings or heterocycle, it is for being unsubstituted or being selected from R respectively by 1 to 9 bSubstituent group replace;
Ar 1And Ar 2Be respectively to be selected from 5 yuan to 10 yuan aromatic carbon rings and heterocycle, it is respectively done for oneself and is unsubstituted or is selected from formula LR respectively by 1 to 3 aThe substituent group of group replaces;
L when occurring separately be respectively be selected from key connect ,-O-,-C (=O)-,-OC (=O)-,-C (=O) O-,-O-C (=O) O-,-S (O) m-,-NR x-,-C (=O) NHR x-,-NHR xC (=O)-,-NR xS (O) m-, S (O) mNR x-and-N[S (O) mR x] S (O) m-; Wherein m is selected from 0,1 and 2; And R xBe respectively to be selected from hydrogen and C when each time occurs 1-C 8Alkyl;
R aWhen occurring, each time be selected from respectively:
(i) hydrogen, halogen atom, cyano group and nitro; And
(ii) C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, C 2-C 8Alkyl ether, 3 yuan to 10 yuan heterocycles, one-(C 1-C 8Alkyl) amino and two-(C 1-C 8Alkyl) amino and (3 yuan to 10 yuan heterocycles) C 1-C 6Alkyl, it is respectively done for oneself and is unsubstituted or is selected from R respectively by 1 to 9 bSubstituent group replace; And
R bBe respectively to be selected from hydroxyl, halogen atom, amino, amino carbonyl, acylamino-, cyano group, nitro, ketone group, C when each time occurs 1-C 8Alkyl, C 1-C 8Alkoxyl, C 1-C 8Alkylthio group, C 1-C 8Alkyl ether, hydroxyl C 1-C 8Alkyl, halogen C 1-C 8Alkyl, phenyl, phenyl (C 1-C 8Alkyl), one-(C 1-C 6Alkyl) amino and two-(C 1-C 6Alkyl) amino, (SO 2) C 1-C 8Alkyl, 5 yuan to 7 yuan heterocycles reach (5 yuan to 7 yuan heterocycles) (C 1-C 8Alkyl).
Term
Chemical compound described herein typically uses the standard name and describes.For the chemical compound with center of asymmetry, it contains whole optical isomeric compound and composition thereof must to understand (unless making separate stipulations).In addition, the chemical compound with carbon-to-carbon double bond can be Z-shaped and E shape, and all chemical compound isomeric compound shape all is contained in scope of the present invention (unless making separate stipulations).When chemical compound existed with various tautomerism shapes, the chemical compound of quoting is non-to only limit to any specific compounds tautomeric, but tends to contain whole tautomeric forms.Some this is sentenced chemical compounds that general formula describes and is comprised variable (R for example 1, n, Ar 1).Unless make separate stipulations, otherwise each variable in this formula is independently to define with other variable, occurs can separating definition more than once any variable when each time occurs in formula.
Term " quinazoline-4-ylamine analogues " is used for containing herein and all can satisfies herein one or more suc as formula the chemical compound of I-IV, and the pharmaceutically acceptable salt and the hydrate of these chemical compounds.These chemical compounds comprise analog, and the wherein theheterocyclic nitrogen atom number of quinazoline core and/or position process modification, and analog wherein each substituent group (being detailed later) is attached at this kind core texture.In other words, the chemical compound of pyrido [2,3-d] pyrimidine-4-base amine, pyrido [3,2-d] pyrimidine-4-base amine, isoquinolyl-1 amine and phthalazines-1-base amine is the scope that belongs to quinazoline-4-ylamine analogues.
" alkyl " vocabulary that is used for herein shows the aliphatic hydrocarbon that straight chain, side chain or ring-type are saturated.Alkyl can key be connected to an atom of molecules of interest inside through the suitable part of any chemistry.Alkyl comprises the alkyl (C that contains 1 to 8 carbon atom 1-C 8Alkyl), contain 1 to 6 carbon atom (C 1-C 6Alkyl) and contain 1 to 4 carbon atom (C 1-C 4Alkyl), for example methyl, ethyl, propyl group, isopropyl, normal-butyl, sec-butyl, the tert-butyl group, amyl group, 2-amyl group, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methyl amyl, cyclopropyl, cyclopropyl methyl, cyclopenta, cyclopentyl-methyl, cyclohexyl, suberyl and norborny." C 0-C 4Alkyl " connection of expression key or C 1-C 4Alkyl; " C 0-C 8Alkyl " connection of expression key or C 1-C 8Alkyl.
In like manner, " thiazolinyl " expression straight or branched thiazolinyl or cycloalkenyl group.Have one or more unsaturated carbon-to-carbon double bond in thiazolinyl inside.Thiazolinyl comprises C 2-C 8Thiazolinyl, C 2-C 6Thiazolinyl and C 2-C 4Thiazolinyl, its each self-contained 2 to 8 carbon atoms, 2 to 6 carbon atoms or 2 to 4 carbon atoms such as vinyl, acrylic or isopropenyl." alkynyl " expression straight or branched alkynyl, it contains one or more unsaturated carbon-carbon bond, and wherein at least one unsaturated bond is a triple bond.Alkynyl comprises C 2-C 8Alkynyl, C 2-C 6Alkynyl and C 2-C 4Alkynyl, it contains 2 to 8 carbon atoms, 2 to 6 carbon atoms or 2 to 4 carbon atoms separately.
" alkoxyl " is used for representing the alkyl, the alkenyl or alkynyl that are connected by the oxo bridge key as previously mentioned herein.Alkoxyl comprises C 1-C 8Alkoxyl, C 1-C 6Alkoxyl and C 1-C 4Alkoxyl, it contains 1 to 8 carbon atom, 1 to 6 carbon atom or 1 to 4 carbon atom respectively.Alkoxyl comprises for example methoxyl group, ethyoxyl, propoxyl group, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, 2-amoxy, 3-amoxy, isoamoxy, neopentyl oxygen, hexyloxy, 2-hexyloxy, 3-hexyloxy and 3-methyl amoxy.
" alkanoyl " vocabulary shows that acyl group is linear, branch or annular arrangement (for example-(C=O)-alkyl).Acyl group comprises C 2-C 8Alkanoyl, C 2-C 6Alkanoyl and C 2-C 4Alkanoyl, it contains 2 to 8,2 to 6 or 2 to 4 carbon atoms respectively." C 1Alkanoyl " expression-(C=O)-and H, be encompassed in " C 1-C 8Alkanoyl " scope.
" alkane ketone " is ketone group, and wherein carbon atom is to be linearity, branch or cyclic alkyl to arrange." C 3-C 8Alkane ketone ", " C 3-C 6Alkane ketone " reach " C 3-C 4Alkane ketone " expression contains the alkane ketone of 3 to 8,6 or 4 carbon atoms respectively.C for example 3Alkane ketone has structural formula-CH 2-(C=O)-CH 3
In like manner, " alkyl ether " expression sees through carbon-carbon bond and is connected to straight chain or branch's ether substituent group.Alkylether radicals comprises C 2-C 8Alkyl ether, C 2-C 6Alkyl ether, and C 2-C 4It contains 2 to 8,6 or 4 carbon atoms respectively alkyl ether.C for example 2Alkylether radicals has structural formula-CH 2-O-CH 3
" alkoxy carbonyl group " vocabulary shows that being coupled to alkoxyl by carbonyl bond (that is has the group of general formula-C (=O)-O-alkyl).Alkoxy carbonyl group comprises C 2-C 8, C 2-C 6And C 2-C 4Alkoxy carbonyl group, it contains 2 to 8,6 or 4 carbon atoms respectively." C 1Alkoxy carbonyl group " expression-C (=O)-and OH, it is to be encompassed in " C 1-C 8Alkoxy carbonyl group " in the scope of a speech.
" alkanoyloxy " is used for representing (that is to have general formula-O-C (=O)-group of alkyl) by oxo bridge binding to alkanoyl herein.Alkanoyloxy comprises C 2-C 8, C 2-C 6And C 2-C 4Alkanoyloxy, it contains 2 to 8,6 or 4 carbon atoms respectively." C 1Alkanoyloxy " be meant O-C (=O)-H, it is to be encompassed in " C 1-C 8Alkanoyloxy " in the scope of a speech.
" C 1-C 8Carbonate " vocabulary shows the alkoxy carbonyl group via oxo bridge base key connection.Change speech, carbonate have general formula-O-C (=O)-the O-alkyl.C 1-C 6Carbonate is generally preferably, C 1-C 4Carbonate is for preferred especially.
" C 1-C 8The carbamic acid root " speech be used for representing to have formula formula-N-C herein (=O)-group of O-alkyl.Usually with C 1-C 6The carbamic acid root is preferred, with C 1-C 4The carbamic acid root is for preferred especially.
Alkyl amino represent to have formula formula-NH-alkyl or-secondary amine or the tertiary amine of N (alkyl) (alkyl), wherein each alkyl can be identical or different.These groups for example comprise one-and two-(C 1-C 8Alkyl) amino, wherein each alkyl is identical or different, contains 1 to 8 carbon atom and-and two-(C 1-C 6Alkyl) amino and one-and two-(C 1-C 4Alkyl) amino.The alkyl amino that the alkyl amino alkyl is represented to connect via alkyl (that is have formula formula-alkyl-NH-alkyl or-alkyl-N (alkyl) (alkyl)) group.This kind group for example for example comprises one-and two-(C 1-C 8Alkyl) amino C 1-C 8Alkyl, one-and two-(C 1-C 6Alkyl) amino C 1-C 6Alkyl and one-and two-(C 1-C 4Alkyl) amino C 1-C 4Alkyl, wherein each alkyl can be identical or different.
" amino carbonyl " vocabulary show acylamino-(that is-(C=O) NH 2).
" halogen " speech comprises fluorine, chlorine, bromine and iodine." haloalkyl " be branch, straight chain or cyclic alkyl by 1 or a plurality of halogen atom replace (" halo C for example 1-C 8Alkyl " contain 1 to 8 carbon atom; " halo C 1-C 6Alkyl " contain 1 to 6 carbon atom).Haloalkyl for example comprise (but non-limiting)-, two-or three-methyl fluoride; One-, two-or three-chloromethyl; One-, two-, three-, four-or pentafluoroethyl group; And one-, two-, three-, four-or pentachloro-ethyl.Typical case's haloalkyl is trifluoromethyl and difluoromethyl.Have no more than 5 or 3 haloalkyls in some chemical compounds provided herein." halogenated alkoxy " vocabulary shows that the haloalkyl as the preamble definition is connected by oxo bridge." halo C 1-C 8Alkoxyl " contain 1 to 8 carbon atom.
Non-ly be used for representing substituent junction point between two letters or intersymbol strigula ("-").For example-CONH 2Be to connect through carbon atom.
" hetero atom " speech is used for representing oxygen, sulfur or nitrogen herein.
" carbocyclic ring " or " carbocylic radical " comprises at least one ring that is formed by carbon-carbon bond fully (being called the carbocyclic ring ring herein), and do not contain heterocyclic ring.Unless make separate stipulations, otherwise that each carbocyclic ring ring of carbocyclic ring inside can be is saturated, fractional saturation or aromatic series.Carbocyclic ring contains 1 to 3 fused rings usually, side goes out ring or volution, and the carbocyclic ring of some specific embodiment contains a ring or two fused rings.Typically, each ring is 3 to 8 yuan of ring (that is C 3-C 8); Quote from C in some specific embodiment 5-C 7Ring.Comprise the carbocyclic ring that fused rings, side go out ring or spiral shell shape ring and be typically 9 to 14 yuan of rings.Some representative carbocyclic rings be cycloalkyl (that is the group that comprises saturated rings and/or fractional saturation ring for example cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, ring octyl group, adamantyl, decahydro-naphthyl, octahydro-indenyl and aforementioned any fractional saturation change, cyclohexenyl group for example), and aromatic group (that is the group that contains at least one aromatic carbon ring ring for example phenyl, benzyl, naphthyl, phenoxy group, benzyloxy, phenacyl, fluorenyl, 2,3 indanyls and 1,2,3,4-tetrahydrochysene-naphthyl).The for example further key of carbon atom that exists in carbocyclic ring ring inside is connected to any of 0,1 or 2 hydrogen atom and/or multiple ring substituents, for example hydroxyl, halogen atom, cyano group, nitro, C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, C 1-C 8Alkoxyl, C 2-C 8Alkyl ether, C 3-C 8Alkane ketone, C 1-C 8Alkylthio group, amino, one-(C 1-C 8Alkyl) amino or two-(C 1-C 8Alkyl) amino, C 3-C 7Cycloalkyl C 0-C 4Alkyl, halo C 1-C 8Alkyl, halo C 1-C 8Alkoxyl, amino C 1-C 8Alkyl, hydroxyl C 1-C 8Alkyl, C 1-C 8Alkanoyl, C 1-C 8Alkoxy carbonyl group ,-COOH ,-C (=O) NH 2, one-or two-(C 1-C 8Alkyl) carboxamido ,-S (O 2) NH 2And/or one-or two-(C 1-C 8Alkyl) sulfonamido.
Some carbocyclic rings of citation herein comprise C 6-C 10Aryl C 0-C 8(that is the carbocyclic ring that wherein comprises at least one aromatic rings is by direct key or passes through C alkyl 1-C 8Alkyl and the group of binding).These groups comprise for example phenyl and 2,3 indanyls, and wherein any is to pass through C 1-C 8Alkyl preferably sees through C 1-C 4The group of alkyl binding.Phenyl is to connect by direct key, or is phenyl C by naming 0-C 8The alkyl of alkyl (for example benzyl, 1-phenyl-ethyl, 1-phenyl-propyl group and 2-phenyl-ethyl) connects.
" heterocycle " or " heterocyclic radical " contains 1 to 3 fused rings, side and goes out ring or volution, and wherein at least one ring is heterocycle (that is one or more annular atoms be hetero atom, all the other annular atomses are carbon).Typically, heterocycle comprises 1-4 hetero atom; In some specific embodiment, each ring of each heterocycle contains 1 or 2 hetero atom.Each heterocycle is generally 3 to 8 yuan of rings (having quoted from 5 to 7 yuan of rings in some specific embodiment), comprises the heterocycle that fused rings, side go out ring or volution and is typically 9 to 14 yuan of rings.Heterocycle can randomly replace with a plurality of substituent groups at nitrogen-atoms and/or carbon atom, and for example preamble is to the described substituent group of carbocyclic ring.Unless make separate stipulations, otherwise heterocycle can be Heterocyclylalkyl (that is each ring is saturated or fractional saturation) or heteroaryl (that is at least one ring in this group is aromatic rings).Heterocyclic radical normally sees through any ring or substituent group atom binding, as long as can obtain stable compound.N binding heterocyclic radical is to see through composition nitrogen-atoms binding." heterocycle C 0-C 8Alkyl " connect or C for seeing through direct key 1-C 8The heterocyclic radical of alkyl binding.(3 yuan to 10 yuan heterocycles) C 1-C 6Alkyl is 3 to 10 yuan the C that sees through 1-C 6The heterocyclic radical of alkyl binding.
Heterocyclic radical for example comprises acridinyl, one nitrogen cyclic group in heptan, the hot cyclic group of one nitrogen, benzimidazolyl, the benzimidazoline base, the benzisothiazole base, the benzoisoxazole base, benzofuranyl, the benzimidazole thiophanate furyl, benzothienyl benzoxazolyl, benzothiazolyl, the benzotriazole base, carbazyl, the benzo tetrazole radical, the NH-carbazyl, carbolinyl, acridinyl, chromanyl, benzopyranyl, the cinnolines base, decahydroquinolyl, dihydrofuran also [2,3-b] oxolane, the dihydro-isoquinoline base, the dihydro tetrahydrofuran base, 1,4-Er Evil-8-a word used for translation-spiral shell [4.5] last of the ten Heavenly stems-8-base, the dithiazine base, furyl, furan is praised base, imidazolinyl, the imidazolidine base, imidazole radicals, indazolyl, the indole thiazolinyl, the indoline base, indolizinyl, indyl, isobenzofuran-base, the isochroman base, iso indazolyl, the isoindoline base, isoindolyl, isothiazolyl isoxazolyl, isoquinolyl, morpholinyl, naphthyridinyl, Decahydroisoquinolinpreparation base oxadiazole base Evil thiazole pyridine base oxazolyl, phenanthridinyl, the phenanthroline base, phenazinyl, phenothiazinyl Fen Evil thiophene is because of basic phenoxazine group, phthalazinyl, piperazinyl, piperidyl, piperidyl, piperidone base, pteridyl, purine radicals, pyranose, the piperazine pyrazinyl, pyrazoles pyridine base, pyrazolinyl, pyrazolyl, pyridazinyl, the pyridine-imidazole base, Bi Ding Bing oxazolyl, the pyrido thiazolyl, pyridine radicals, pyrimidine radicals, the Pyrrolizidine base, the Pyrrolizidine ketone group, pyrrolinyl, pyrrole radicals, quinazolyl, quinolyl quinoxalinyl, the quinuclidine base, tetrahydro isoquinolyl, tetrahydric quinoline group, tetrazole radical, the thiadiazine base, thiadiazolyl group, thianthrene group, thiazolyl, the thieno thiazolyl, thiophene Bing oxazolyl, the Thienoimidazole base, thienyl, sulfur phenenyl, tetrahydro-1,4-thiazine base and variation example thereof, wherein sulphur atom is through oxidation, triazine radical, oxa-anthryl and aforementioned arbitrary group are replaced by 1 to 4 aforementioned substituent group.
Some heterocyclic radicals are 3 yuan to 10 yuan or 5 yuan to 10 yuan groups, and it contains a heterocycle or two fused rings or volution, randomly replaces as described above.(C 3-C 10) Heterocyclylalkyl for example comprises piperidyl, piperazinyl, Pyrrolizidine base, a nitrogen cyclic group in heptan, 1,4-Er Evil-8-a word used for translation-spiral shell [4.5] last of the ten Heavenly stems-8-base, morpholinyl, tetrahydro-1,4-thiazine base, and 1,1-diketo-tetrahydro-1,4-thiazine-4-base, and wherein aforementioned each group is selected from halogen atom, hydroxyl, C respectively by 1 to 6 (preferred 1 to 4) 1-C 4Alkyl, C 1-C 4Alkoxyl, halo C 1-C 4Alkyl, halo C 1-C 4Alkoxyl, C 1-C 4Alkyl-carbonyl and C 1-C 4The group that the substituent group of alkoxy carbonyl group replaces.In some specific embodiment, Heterocyclylalkyl can be 4 yuan to 7 yuan Heterocyclylalkyl C 0-C 4Alkyl.These groups comprise aforementioned 4 yuan to 7 yuan Heterocyclylalkyls and see through direct key or C 1-C 4The alkyl binding.
Some heteroaromatics comprise 5 yuan to 10 yuan heteroaryl C 0-C 8(heterocyclic radical that promptly wherein comprises at least one aromatic rings is by direct key or C to alkyl 1-C 8The group that alkyl connects).This kind group comprises for example heteroaryl of preamble citation, and wherein aforementioned arbitrary group passes through C 1-C 8Alkyl, C 1-C 6Alkyl or C 1-C 4The group that alkyl connects.Representational heteroaromatic is azoles octyl group, pyridine radicals, pyrimidine radicals, imidazole radicals, tetrazole radical, 3, and 4-dihydro-1H-isoquinolin-2-base and wherein aforementioned each group are to pass through C 1-C 4The group that alkyl connects.
" substituent group " is used for representing being covalently linked to the molecular moiety of an atom of molecules of interest inside herein.For example " ring substituents " can be halogen atom for example discussed herein, alkyl, haloalkyl or other group part, and it is to be covalently linked to ring members atom (being preferably carbon atom or nitrogen-atoms).Therefore " replacement " vocabulary shows the hydrogen atom with aforementioned substituent group displacer molecule structure, is no more than the valence mumber of specified atom, can obtain chemical property stable compound (also can be separated, decision feature and the active chemical compound of test organism) by replacing.
The group that " randomly is substituted " is replaced by one or more suitable non-hydrogen groups (can be identical or different) for being unsubstituted or can utilizing the position to be typically 1,2,3,4 or 5 position at one or more.This kind randomly substituent group for example comprises hydroxyl, halogen atom, cyano group, nitro, C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, C 1-C 8Alkoxyl, C 2-C 8Alkyl ether, C 3-C 8Alkane ketone, C 1-C 8Alkylthio group, amino, one-or two-(C 1-C 8Alkyl) amino, halo C 1-C 8Alkyl, halo C 1-C 8Alkoxyl, C 1-C 8Alkanoyl, C 1-C 8Alkanoyloxy, C 1-C 8Alkoxy carbonyl group ,-COOH ,-CONH 2, one-or two-(C 1-C 8Alkyl) carboxamido ,-SO 2NH 2, and/or one-or two-(C 1-C 8Alkyl) sulfonamido and carbocyclic ring family base or heterocyclic radical.Some randomly substituent groups are replaced by 0 to 3 independent substituent group of selecting.
" VR1 ", " the class Rhizoma et radix valerianae receptor of first type " reach speech such as " capsaicin receptors " and exchange use herein.Unless make separate stipulations, otherwise rat VR1 receptor and people VR1 receptor (for example GenBank access numbering AF327067, AJ277028 and NM_018727 contained in these terms; Some people VR1 cDNAs sequences are provided at United States Patent (USP) the 6th, 482, encoding amino acid sequence shown in No. 611 SEQ ID NOs:1-3 and SEQ ID NOs:4 and 5), and the being seen thing that is both of other species.
" VR1 regulator " is also referred to as herein to " regulator " is the chemical compound of a kind of scalable VR1 activation and/or the transduction of VR1-media signal.The VR1 regulator can be VR1 agonist or VR1 antagonist, but in order to reach some purpose described herein, the VR1 regulator preferably suppresses be bonded to the VR1 activation that VR1 causes via class vanilloid ligand seat agonist (for example capsaicin or capsaicin analog such as Ovani (olvanil) or RTX).If K at VR1 iBe less than 1 μ M, preferably less than 100nM, 10nM or 1nM, then regulator is with " high affinity " combination.Be determined at the K of VR1 iRepresentativeness calibrating analyze herein that embodiment 5 provides.If detect to such an extent that the signal transduction (the representativeness calibrating of for example using embodiment 6 to provide is analyzed) that class vanilloid ligand seat is bonded to VR1 and/or VR1 media can be provided regulator, then this regulator is regarded as antagonist; Usually this kind antagonist can suppress the VR1 activation, the IC that the calibrating that having embodiment 6 provides is analyzed 50Value is less than 1 μ M, preferably less than 100nM and be more preferably less than 10nM or 1nM.The VR1 antagonist comprises neutral antagonist and anti-agonist.Preferred regulator can not suppress human epidermal growth factor (EGF) receptor Tyrosine kinase activity in fact and (that is examine and determine the IC of analysis at the EGF receptor 50Be greater than 1 μ M, be preferably greater than 100 μ M or 10 μ M).More preferably but regulator can not suppress the EGF receptor active with detection mode.Detection is well-known for industry to the calibrating analysis that the EGF receptor suppresses effect, comprises people such as Carpenter (1979) biochemistry periodical 254:4884, and United States Patent (USP) the 5th, 654,307 and 6,169, No. 091 described calibrating analysis.
" the anti-agonist " of VR1 can suppress the active chemical compound in class vanilloid ligand seat at VR1 for a kind of, not having in the presence of the class of the interpolation vanilloid ligand seat, can reduce the VR1 activity to being lower than its benchmark level of activity.The anti-agonist of VR1 also can suppress combining of class vanilloid ligand seat and VR1.Chemical compound suppresses the ability of class vanilloid ligand seat in conjunction with VR1, but mat in conjunction with calibrating analyze that embodiment 5 for example enumerates in conjunction with the calibrating assay determination.The benchmark activity of VR1 and VR1 activity can be by the calibrating of calcium mobility assay determination, for example the calibrating assay determinations of embodiment 6 by reducing having the VR1 antagonist.
" neutral antagonist " of VR1 is a kind of class vanilloid ligand seat and active chemical compound of VR1 of suppressing, but the primary activity that can significantly not change receptor is (that is in embodiment 6 described calcium mobility calibrating analyses, in the presence of no class vanilloid ligand seat, the active reduction of VR1 is no more than 10%, 5% or 2%; Preferably there be not detectable active the reduction).The neutral antagonist of VR1 can suppress class vanilloid ligand seat and be bonded to VR1.
Be used for herein VR1 " agonist " for can promote the chemical compound that receptor active is higher than receptor benchmark level of activity.
" class vanilloid ligand seat " is capsaicin or any capsaicin analog, and it comprises a benzyl ring, and described benzyl ring is bonded to adjacent annulus carbon by two oxygen atoms, and it is bonded to VR1, has K i(measuring as described here) is not higher than 10 μ M.Class vanilloid ligand seat agonist comprises capsaicin, Ovani, N-arachidonic acyl group, dopamine and RTX (RTX).Class vanilloid ligand seat antagonist comprises capsaicin receptor blocker and iodo-RTX.
" prodrug " is a kind of structural requirement that can't satisfy chemical compound provided herein fully, but can produce quinazoline-4-ylamine analogues through revising in vivo after giving the patient.For example prodrug can be the acylated derivatives of chemical compound provided herein.Prodrug comprises following chemical compound, and wherein hydroxyl, amino or sulfydryl key are connected to any group, and this group can be cleaved when giving mammalian subject and be formed free state hydroxyl, amino or sulfydryl respectively.Prodrug for example comprises the alcohol functional group of (but non-limiting) chemical compound provided herein inside and acetic acid, formic acid and the benzoic acid derivative of amino-functional base.
" patient " is any individuality that uses VR1 regulator provided herein to handle.The patient comprises the mankind and other animal for example companion animals (as dog and cat) and animals.The patient one or more may occur capsaicin receptor is regulated the disease symptoms respond (for example pain, be exposed to class vanilloid ligand seat, scratch where it itches, urinary incontinence, breathing disease, cough and/or have the hiccups), also may not contain these symptoms (promptly being treated to preventative) at all.
The VR1 regulator
As described above, the invention provides the VR1 regulator (is the chemical compound of the signal transduction of scalable VR1 media; But be preferably the chemical compound that also is bonded to VR1) with detection mode.The VR1 regulator also can be used for the many-sided VR1 of adjusting activity, comprise treatment (i) pain (for example pain of neuropathy degeneration pain or peripheral neural media), (ii) be exposed to capsaicin, (iii) be exposed to acid, heat, light, teargas, air pollution, pepper spray agent or relevant chemical agent, (iv) respiratory disorder is for example panted or Chronic obstructive pulmonary disease, (v) scratch where it itches, (vi) urinary incontinence (is vii) coughed or is had the hiccups and/or (viii) fat.The VR1 regulator also can be used for multinomial test tube test calibrating and analyzes (for example the receptor active calibrating is analyzed) as the probe that detects with location VR1, and as at ligand is analyzed in conjunction with calibrating and VR1 media signal transduction calibrating is analyzed standard substance.
VR1 regulator provided herein is the quinazoline-4-ylamine analogues that is substituted, its be with nanomolar concentration (promptly time micro-molar concentration) but concentration regulate capsaicin with detection mode and be bonded to VR1, preferably at inferior nanomolar concentration, more preferably be lower than 100pM or even the concentration adjustment capsaicin that is lower than 20pM be bonded to VR1.This kind regulator is preferably non-capsaicin analog (being that it does not contain the benzyl ring that two oxygen atom keys are connected to the adjacent annulus atom).Preferred regulator is not for having the active VR1 antagonist of detectable agonist in embodiment 6 described calibratings are analyzed.In some specific embodiment, this kind regulator further is bonded to VR1 with high affinity, and can not suppress human EGF receptor Tyrosine kinase activity in fact.
The present invention is that part is based on finding to have micromolecule (and pharmaceutically acceptable salt, hydrate and prodrug) the scalable VR1 activity of general formula I.In some specific embodiment, be not more than 2 for N among W, Y and the Z.Representational quinazoline-4-ylamine analogues comprises that wherein U, V, W, X, Y and Z are applicable to the chemical compound of any specific embodiment that table 1 is enumerated (but non-limiting).
Table I
Representative quinazoline-4-ylamine analogues core texture
????U ????V ????X ????W ????Y ????Z
????CR 2 ????N ????CH ????CH ????CH ????CH
????CR 2 ????CH ????N ????CH ????CH ????CH
????CR 2 ????N ????N ????CH ????CH ????CH
????N ????CH ????N ????CH ????CH ????CH
????CR 2 ????N ????CH ????CH ????N ????CH
????CR 2 ????CH ????N ????CH ????N ????CH
????CR 2 ????N ????N ????CH ????N ????CH
????N ????CH ????N ????CH ????N ????CH
????CR 2 ????N ????CH ????CH ????CH ????N
????CR 2 ????CH ????N ????CH ????CH ????N
????CR 2 ????N ????N ????CH ????CH ????N
????N ????CH ????N ????CH ????CH ????N
????CR 2 ????N ????CH ????N ????CH ????CH
????CR 2 ????CH ????N ????N ????CH ????CH
????CR 2 ????N ????N ????N ????CH ????CH
????N ????CH ????N ????N ????CH ????CH
????CR 2 ????N ????CH ????N ????CH ????N
????CR 2 ????CH ????N ????N ????CH ????N
????CR 2 ????N ????N ????N ????CH ????N
????N ????CH ????N ????N ????CH ????N
????CR 2 ????N ????CH ????CH ????N ????N
????CR 2 ????CH ????N ????CH ????N ????N
????CR 2 ????N ????N ????CH ????N ????N
????N ????CH ????N ????CH ????N ????N
In formula I-IV, R 1Be preferably hydrogen, C 1-C 4Alkyl or halo C 1-C 4Alkyl, with hydrogen for preferred especially.For example V and X are all N.In some specific embodiment, one of W, Y or Z are N, and all the other are CH, or W, Y and Z all are all CH.
In some specific embodiment, the R of formula I and II 2If be hydrogen, amino, hydroxyl, halogen atom when existing or randomly be substituted-(CH 2) nNH 2,-(CH 2) nNH (C 1-C 8Alkyl) ,-(CH 2) nN (C 1-C 8Alkyl) 2,-(CH 2) n(5-unit to 8-unit heterocyclic radical) ,-(CH 2) nOH ,-(CH 2) nO (C 1-C 8Alkyl).The group that randomly is substituted for example comprises the group that is unsubstituted and is selected from halogen atom, cyano group, hydroxyl, amino, one-and two-(C respectively by 1 to 4 1-C 6Alkyl) amino, C 1-C 6Alkyl, and halo C 1-C 6The group that the substituent group of alkyl replaces.Heterocyclylalkyl comprises that wherein Heterocyclylalkyl comprises nitrogen-atoms or oxygen atom is connected directly to-(CH 2) n
In some specific embodiment, suc as formula the Ar of I-IV chemical compound 1And Ar 2It can randomly replace to be selected from 5-unit to 7-unit aromatic carbon ring and heterocycle respectively.Ar for example 1And Ar 2Can be selected from phenyl and 6-unit heteroaromatic respectively, it is replaced by 0,1 or 2 substituent group separately.In some specific embodiment, Ar 1Be phenyl or pyridine radicals, its respectively do for oneself be unsubstituted or by 1,2 or 3 as described above substituent group replace; Preferred these substituent groups (if having) can be selected from halogen atom, hydroxyl, cyano group, amino, nitro ,-and two-(C respectively 1-C 6Alkyl) amino, C 1-C 6Alkyl, halo C 1-C 6Alkyl, C 1-C 6Alkoxyl and halo C 1-C 6Alkoxyl.Ar for example 1One be can contain and halogen atom, C are selected from 1-C 6Alkyl, C 1-C 6Alkoxyl, halo C 1-C 6Alkyl, and halo C 1-C 6The substituent group of alkoxyl.If have one or more Ar 1Substituent group, then at least one substituent group is preferably placed at ortho position (Ar for example 1Can be the phenyl that is substituted in 2 positions, or be substituted in the 2-pyridine radicals of 3 positions).Ar 1Group comprises (but non-limiting) pyridine-2-base, 3-methyl-pyridine-2-base, 3-trifluoromethyl-pyridine-2-base and 3-halogen-pyridine-2-base.
In some specific embodiment, Ar 2Be phenyl or pyridine radicals, its respectively do for oneself be unsubstituted or by 1 or 2 as described above substituent group replace.In some specific embodiment, a substituent group is positioned at 6 yuan of Ar 2The para-position position; Among the formula II ,-SO 2-R 7Be preferably placed at para-position, among formula I, III and the IV, randomly substituent group is preferably placed at this para-position position.Ar randomly 2Substituent group is aforementioned substituent group, for example comprises wherein R aBe respectively to be selected from following group when each time occurs: (i) hydrogen, halogen atom, cyano group and nitro; And (ii) C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl and 3-unit to 10-unit heterocycle, it randomly is selected from hydroxyl, halogen atom, C respectively by 1 to 9 separately 1-C 6Alkyl and halo C 1-C 6The substituent group of alkyl replaces.Preferred R aPart comprises halogen atom, hydroxyl, cyano group, amino, one-and two-(C 1-C 6Alkyl) amino, C 1-C 6Alkyl, halo C 1-C 6Alkyl, C 1-C 6Alkoxyl, halo C 1-C 6Alkoxyl, C 2-C 6Alkyl ether, C 1-C 6Alkanoyl ,-(SO 2) R n,-NR xS (O) m, and-N (S (O) m) 2Wherein m is 1 or 2, R xBe hydrogen or C 1-C 6Alkyl and R aBe C 1-C 6Alkyl, halo C 1-C 6The N-of alkyl or 5-unit to 10-unit connects heterocyclic radical, each R aRandomly be selected from R respectively by 1 to 4 aSubstituent group replace.Preferred Ar 2Substituent group comprises C 1-C 4Alkyl, halo C 1-C 4Alkyl, and formula-(SO 2) R aGroup, wherein R aBe C 1-C 4Alkyl or halo C 1-C 4Alkyl.Ar 2Group comprises phenyl, pyridine radicals, pyridazinyl, pyrimidine radicals, piperazine pyrazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, reaches thiadiazolyl group, and it randomly is selected from halogen atom, cyano group, C respectively by 1 or 2 separately 1-C 6Alkyl, halo C 1-C 6Alkyl, C 1-C 6Alkoxyl, halo C 1-C 6Alkoxyl ,-SO 2-R aAnd-SO 2NR x-R aSubstituent group replace.Preferred Ar 2Base is phenyl, pyridine radicals, isoxazolyl, thiadiazolyl group, reaches pyrazolyl, and it is randomly by halogen atom, C 1-C 4Alkyl or halo C 1-C 4Alkyl replaces.In some specific embodiment, Ar 2Be phenyl or pyridine radicals, it randomly is selected from halogen atom, cyano group, C respectively by 1 or 2 separately 1-C 4Alkyl, halo C 1-C 4Alkyl, C 2-C 4Alkyl ether, C 1-C 4Alkanoyl, and formula-(SO 2) R aGroup (R wherein aBe C 1-C 6Alkyl or halo C 1-C 6Alkyl) substituent group replaces.Ar 2Group comprises (but non-limiting) phenyl, 2-pyridine radicals and 3-pyridine radicals; its each comfortable 4-position is by halogen atom, cyano group, methyl, ethyl, propyl group, isopropyl, the tert-butyl group, trifluoromethyl, 2; 2; 2-trifluoroethyl, 2; 2; 2-three fluoro-1-methyl-ethyls, methane sulfonyl, ethane sulfonyl, propane sulfonyl, propane-2-sulfonyl, trifluoromethane sulfonyl group or 2,2,2-HFC-143a sulfonyl replaces.
In the some specific embodiment of formula II chemical compound, Ar 2Be phenyl or pyridine radicals, randomly be selected from halogen atom, cyano group, C respectively by 1 or 2 1-C 6Alkyl, and halo C 1-C 6The substituent group of alkyl replaces; And Ar 1Be phenyl or pyridine radicals, randomly by halogen atom, C 1-C 6Alkyl, halo C 1-C 6Alkyl, C 1-C 6Alkoxyl or halo C 1-C 6Alkoxyl replaces.Among the formula II, be connected to SO 2Ar 2Carbon atom preferably separates at least one annular atoms and preferred two annular atomses with the carbon atom that is connected to N.Change speech, for Ar wherein 2Be the specific embodiment of phenyl, SO 2Preferably be positioned at para-position (4).In some specific embodiment, R 7Be C 1-C 6Alkyl, halo C 1-C 6Alkyl, amino, one-or two-(C 1-C 6Alkyl) amino or non-aromatic heterocycle (for example morpholinyl, piperidyl, piperazinyl or Pyrrolizidine base) randomly replaces as described above.
In some specific embodiment, the R of formula III 3And R 4Be respectively to be selected from (i) hydrogen or (ii) C separately 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, C 3-C 8Alkane ketone, C 1-C 8Alkanoyl, C 2-C 8Alkyl ether, C 6-C 10Aryl C 0-C 8Alkyl, the heterocycle C of 5-unit to 10-unit 0-C 8Alkyl, and-(SO 2) C 1-C 8Alkyl, it randomly is selected from R respectively by 1 to 9 separately bSubstituent group replace.In other specific embodiment, R 3And R 4Be respectively to be selected from (i) hydrogen and (ii) C separately 1-C 8Alkyl, C 2-C 8Thiazolinyl, phenyl C 0-C 4Alkyl, 2,3 indanyl C 0-C 4Alkyl, the heteroaryl C of 5-unit to 6-unit 0-C 4The Heterocyclylalkyl C of alkyl and 4-unit to 7-unit 0-C 4Alkyl, it randomly is selected from hydroxyl, halogen atom, amino, C respectively by 1 to 4 separately 1-C 6Alkyl, halo C 1-C 6Alkyl, C 1-C 6Alkoxyl, and halo C 1-C 6The substituent group of alkoxyl replaces.Representational R 3And R 4Group comprises C 1-C 6Alkyl, C 2-C 6Thiazolinyl, the heterocycle C of 5-unit to 7-unit 0-C 4Alkyl, C 2-C 6Alkyl ether, 2,3 indanyls, benzyl, 1-phenyl-ethyl, 1-phenyl-propyl group, and 2-phenyl-ethyl, it is respectively done for oneself and 5 replaces or be selected from hydroxyl, halogen atom and C respectively by 1 to 3 1-C 4The substituent group of alkyl replaces.R for example 3And R 4In at least one be pyridine radicals C 0-C 4Alkyl, pyrimidine radicals C 0-C 4Alkyl, imidazole radicals C 0-C 4Alkyl or tetrazole radical C 0-C 4Alkyl, it is replaced by 0,1 or 2 substituent group separately.In addition, R 3And/or R 4Can be engaged to R 5Or R 6Group is (together with R 3And R 4Be the N that key connects, and between N and R 5Or R 6Between any carbon atom) form randomly the heterocycle that replaces, for example 5-unit is to 7-unit's monocycle base or bicyclic group.
In other specific embodiment, the R of formula III 3And/or R 4Can form the heterocycle that randomly replaces.R for example 3And R 4The N that can be connected with its key is in conjunction with forming a heterocycle that randomly replaces; Or R 3Or R 4Can be engaged to R 5Or R 6Part forms the heterocycle that randomly replaces.Under any situation, as a result the heterocycle of gained for example be 4-unit or 5-unit to 10-unit's monocyclic groups or bicyclic radicals, this monocyclic groups or bicyclic radicals are randomly replaced (for example 1 to 4 substituent group or 0,1 or 2 substituent group replace) by 0 to 4 substituent group.In some specific embodiment, each substituent group is respectively to be selected from hydroxyl, halogen atom, C 1-C 4Alkyl, halo C 1-C 4Alkyl, C 1-C 4Alkoxyl, halo C 1-C 4Alkoxyl, C 1-C 4Alkanoyl, C 1-C 4Alkoxy carbonyl group, amino carbonyl, heterocycle C 0-C 8Alkyl, and heterocycle C 1-C 8Alkoxy carbonyl group.In some specific embodiment, these substituent groups are low-carbon alkyl such as methyl and/or ethyl.
Comprise R 3And/or R 4Heterocyclic radical can be heteroaryl, it comprises aromatic rings (for example randomly replace acridinyl, benzimidazoline base, benzimidazolyl, benzotriazole base, carbazyl, cinnolines base, indazolyl, indoline base, indyl, isoquinolyl, quinoxalinyl, naphthyridinyl, phenanthridinyl, phenazinyl, phenothiazinyl, phenoxazine group, phthalazinyl, pteridyl, purine radicals, quinolyl, quinoxalinyl, quinazolyl, tetrahydro isoquinolyl or tetrahydric quinoline group).One of them heteroaryl is 3,4-dihydro-1H-isoquinolin-2-base.In addition, heterocycle can be randomly the Heterocyclylalkyl that replaces for example a nitrogen cyclic group in heptan, azoles octyl group, decahydroquinolyl, 1,4-Er Evil-8-a word used for translation-spiral shell [4.5] last of the ten Heavenly stems-8-base, imidazolidine base, imidazolinyl, morpholinyl, piperidyl, piperazinyl, pyridazinyl, pyrazoles pyridine base, pyrazolinyl, Pyrrolizidine base, pyrrolinyl, tetrahydro-1,4-thiazine base or 1,1-diketo-tetrahydro-1,4-thiazine-4-base.Can be by R 3With R 4The representative heterocycle that forms comprises a nitrogen ring in heptan that (but non-limiting) randomly be substituted, the hot ring of a nitrogen, dihydro-isoquinoline, imidazoles, morpholine, octahydro quinoline, piperazine, piperidines, and Pyrrolizidine.Can be by R 3Or R 4Combination R 5Or R 6The heterocycle that forms comprises piperidines and the Pyrrolizidine that (but non-limiting) randomly is substituted.
The R of formula III 5And R 6The C that in some specific embodiment, is respectively (when each time occurs, being respectively) hydrogen or randomly replaces 1-C 6Alkyl; In addition or in addition, any R 5Or R 6Can with any another R 5Or R 6Engage and form a 5-unit that randomly replaces to 7-unit cycloalkyl, or (as the preamble discussion) and R 3Or R 4Engage and form the heterocycle that randomly replaces.
In formula IV, (in some specific embodiment) R 3Be (i) hydrogen or (ii) C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, C 3-C 8Alkane ketone, C 2-C 8Alkyl ether, C 6-C 10Aryl C 0-C 8The heterocycle C of alkyl or 5-unit to 10-unit 0-C 8Alkyl, it randomly is selected from R respectively by 1 to 9 separately bSubstituent group replace.In other specific embodiment, the R of formula IV 3Be (i) hydrogen or (ii) C 1-C 6Alkyl, C 2-C 6Alkyl ether, phenyl C 0-C 4Alkyl, the heteroaryl C of 5-unit to 6-unit 0-C 4The Heterocyclylalkyl C of alkyl or 4-unit to 7-unit 0-C 4Alkyl, it randomly is selected from hydroxyl, halogen atom, amino, C respectively by 1 to 4 separately 1-C 6Alkyl, halo C 1-C 6Alkyl, C 1-C 6Alkoxyl, and halo C 1-C 6The substituent group of alkoxyl replaces.Representational R 3Base comprises hydrogen, C 1-C 4Alkyl, C 1-C 4Alkyl ether and benzyl, it is respectively done for oneself and is unsubstituted or is selected from hydroxyl, halogen atom and C respectively by 1 to 3 1-C 4The substituent group of alkyl replaces.In addition, R 3Can be engaged to R 5Or R 6Group is (together with R 3The O that institute's key connects, and any is between O and R 5Or R 6Between carbon atom) and form a heterocycle that randomly replaces, for example 5-unit is to 10-unit's monocycle base or bicyclic group.The gained heterocycle can be for example (for example 0,1 or 2) individual hydroxyl, halogen atom, C of being selected from respectively by 0 to 4 as a result 1-C 4Alkyl, halo C 1-C 4Alkyl, C 1-C 4Alkoxyl, halo C 1-C 4Alkoxyl, C 1-C 4Alkanoyl, C 1-C 4Alkoxy carbonyl group, amino carbonyl, heterocycle C 0-C 8Alkyl, and heterocycle C 1-C 8The substituent group of alkoxy carbonyl group replaces.
In some formula IV specific embodiment, R 5And R 6The C that when each time occurs, can be respectively hydrogen or randomly replace 1-C 6Alkyl; In addition or in addition, any R 5Or R 6Can be engaged to any another R 5Or R 6And form a 5-unit that randomly replaces, or (as the preamble discussion) and R to the first cycloalkyl of 7- 3Engage and form a heterocycle that randomly replaces.In some specific embodiment, each R 5And R 6Be hydrogen.N is 1,2 or 3, is good with 1 in some specific embodiment.
Some preferred chemical compounds satisfy at least one among formula Ia, IIa, IIIa or the IVa, and variable wherein is respectively as preamble I, II, III and IV to be defined:
Formula Ia formula IIa
Formula III a formula IVa
The chemical compound as I-IV of representative formula comprises, but is not restricted to the chemical compound that embodiment 1-3 specifies.The specific compound of quoting from the obvious example is only as representative compounds, but not intention limits scope of the present invention.In addition as previously mentioned, all The compounds of this invention can be hydrate, free state alkali or its pharmaceutically acceptable acid-addition salts form existence.
The quinazoline that is substituted-4-ylamine analogues provided herein changes the VR1 activity that bring out at (adjusting) class vanilloid ligand seat in detectable mode, as use standard test tube test VR1 ligand to analyze in conjunction with calibrating and/or function calibrating assay determination, the function calibrating is analyzed for example for the calibrating of calcium mobility is analyzed, the dorsal root ganglion calibrating is analyzed or live test pain relief calibrating is analyzed.The calibrating of " the VR1 ligand is analyzed in conjunction with calibrating " described herein expression standard test tube test receptors bind is analyzed, for example provide, and " calibrating of calcium mobility is analyzed " (be also referred to as is " the signal transduction calibrating is analyzed ") can use the method for embodiment 6 to carry out by embodiment 5.In brief, in order to appraise through comparison the combination of VR1, the calibrating that can be at war with is analyzed, wherein the VR1 preparation be with through labelling (for example 125I) the test compound co-cultivation of VR1 agonist and un-marked.The calibrating analysis that provides herein, the VR1 of use is preferably mammals VR1, more preferably the mankind or rat VR1.Receptor can show or show with natural way by recombination form.The VR1 formulation example is as the film preparation that derives from HEK293 cell or Chinese hamster ovary celI that can recombination form shows human VR1 (for example United States Patent (USP) the 6th, 482, the VR1 sequence that provides for No. 611) is provided.
But, will cause being bonded to the labelled amount of VR1 preparation, with respect to the increase and decrease of bonded labelled amount in the presence of this chemical compound of nothing with the chemical compound co-cultivation that is bonded to VR1 with detection mode adjusting class vanilloid ligand seat.Preferred this kind chemical compound has K in embodiment 5 described VR1 ligands are analyzed in conjunction with calibrating iLess than 1 μ M, be more preferably less than 500nM, 100nM, 20nM, 10nM or 1nM at VR1.Usually preferably in analyzing, this kind calibrating reduces the chemical compound that labelling is bonded to the VR1 amount of formulation.
As previously mentioned, the VR1 agonist compounds is preferred in some specific embodiment.These chemical compounds move in the calibrating analysis at the calcium of the standard test tube test VR1 media that embodiment 6 provides, and have IC 50Value is 1 μ M or following, preferably about 100nM or following, 10nM or following or 1nM or following.In brief, express the cell of capsaicin receptor and compound of interest and cellular calcium concentration indicator [film Permeability calcium sensitivity dyestuff for example, for example (the two all derives from for example molecular probe company, and the Oregon is Jin Shi still, and it is when being bonded to Ca for Fluo-3 or Fura-2 ++The time produce fluorescence separately)] contact.This kind contact preferably via cell in inclusion compound and indicator any or the two carry out in the buffer or the culture medium of solution.Contact is kept one section and is enough allowed dyestuff to enter the time (for example 1-2 hour) of cell.Cell removes excess dye through washing or filtration, contacts class Rhizoma et radix valerianae receptor agonists (for example capsaicin, RTX or Ovani) then, is preferably equaling IC 50The concentration contact of concentration, and measure fluorescence reaction.When cells contacting VR1 agonist compounds, and when cells contacting class Rhizoma et radix valerianae receptor agonists, the cell of contact agonist in the presence of no test compound relatively, fluorescence reaction is reduction at least 20% usually, preferably at least 50% reaches more preferably at least 80%.In addition or in addition, chemical compound can use the live test pain relief calibrating that the calibrating of cultivation dorsal root ganglion is analyzed and/or embodiment 10 provides that provides as embodiment 9 to analyze and appraise through comparison compound activity.Chemical compound provided herein is preferably analyzed in one or more of this kind function calibratings has statistically evident specificity effect to the VR1 activity.
In some specific embodiment, regulator provided herein can not regulated ligand in fact and be bonded to other cell surface receptor, for example EGF receptor Tyrosine kinases or niacin acetylcholinergic receptor.In other words, these regulators can not suppress the cell surface receptor activity in fact, and for example hEGF (EGF) receptor Tyrosine kinase activity or niacin acetylcholine receptor activity are (at the IC of this kind receptor 50Or IC 40Be preferably greater than 1 μ M, and most preferably greater than 10 μ M).But preferred regulator 0.5 μ M, 1 μ M or more preferably 10 μ M concentration can not suppress EGF receptor active or niacin acetylcholine receptor activity with detection mode.Measure calibrating that the EGF receptor suppresses and analyze to industry as everyone knows, comprise people such as Carpenter (1979) biochemistry periodical, 254:4884 and United States Patent (USP) the 5th, 654,307 and 6,169, No. 091 and WO 95/19774 are described.Measure the calibrating analysis that the niacin acetylcholinergic receptor suppresses (IC for example 40) also be that industry is well-known, comprise that Liu and Simon (1997) neuroscience letters 228:29 is described.
Preferred The compounds of this invention does not have stability and stabilization.Change speech, in being provided, the zooscopy pattern of pain relief (for example the pattern that provides of embodiment 10) herein is the enough chemical compound dosage of the lowest dose level twice of generation analgesic effect, analyze (using the described methods of people (1989) toxicology 49 (2-3): 433-9 such as Fitzgerald) in calm zooscopy pattern calibrating and only cause of short duration calm (promptly continue be no more than pain relief persistent period 1/2), or preferably there is no the significantly calm effect of statistics.Preferred 5 multiple doses that enough produce the quelling lowest dose level can not produce statistically evident calm effect.Chemical compound more preferably provided herein is at the vein dosage that is lower than 25 milligrams (preferably being lower than 10 mg/kg) or can not produce calm at the oral dose that is lower than 140 mg/kg (preferably being lower than 50 mg/kg, more preferably less than 30 mg/kg).
If have required, chemical compound provided herein can be assessed some pharmacological propertieses and comprise, but be not limited to, the oral bioavailability rate (preferred compound be oral can be by biological utilisation to allowing to be lower than 140 mg/kg at oral dose, preferably be lower than 50 mg/kg more preferably less than 30 mg/kg again more preferably less than 10 mg/kg, reach the oral dose that most preferably is lower than 0.1 mg/kg more preferably less than 1 mg/kg again, allow to reach the treatment valid density of chemical compound), toxicity (preferred compound is nontoxic when giving individuality for regulating consumption when the capsaicin receptor), side effect (preferred compound is when the placebo that can match in excellence or beauty in the side effect that produces when giving individuality with the treatment effective dose), the serum albumin combination, and (preferred compound has in vitro, and the half-life equals the in vivo half-life in vivo to reach in vitro the half-life, allow 4 administrations every day, preferred 3 administrations every day, more preferably 2 administrations every day and most preferably administration once a day).In addition, it is required when regulating CNS VR1 active treatment pain that the different penetrance of blood brain barrier are chemical compound, therefore aforementioned total every day, oral dose can provide this kind to be adjusted to the treatment significant degree, and the pain of using low brain compound concentration to be used for treating peripheral nerve conduction simultaneously is preferred (being that this kind dosage can not provide enough significantly adjusting VR1 active chemical compound brain concentration (for example CSF concentration)).The well-known customary calibrating of industry is analyzed and be can be used to appraise through comparison these character, and identification is used for the excellent chemical compound of special-purpose.For example be used to predict that the calibrating analysis of biological utilisation comprises that striding people's enterocyte monolayer comprises the transhipment of Caco-2 cell monolayer.Chemical compound can be by the brain concentration prediction of chemical compound at the laboratory animal that gives this chemical compound (for example intravenous injection) to the penetrance in the blood brain barrier at human body.Serum proteins are in conjunction with examining and determine analyses and prediction by albumin bound.The chemical compound half-life is to be inversely proportional to the compound administration frequency.The test tube of the chemical compound test half-life can as described in the embodiment 7 herein by the calibrating analyses and prediction of microsome half-life.
Toxicity and side effect can be used any standard method comparation and assessment.Usually " nontoxic " speech be used for should understanding herein be the expression relative meaning, any material of intention expression gives mammals (being preferably the mankind) by Food and Drug Administration (" FDA "), or meet set standard, can check and approve by FDA and be used for mammals (preferred human).The influence calibrating analysis and evaluation that the pair cell ATP that toxicity can use embodiment 8 to provide makes.Other available calibrating analysis comprises that antibacterial back mutation calibrating analyzes for example A Misi test (Ames test), and the standard monster takes place that calibrating is analyzed and tumor calibrating takes place is analyzed.Preferably give chemical compound described herein and can not cause heart QT prolongation (being the detecting ECG of mat guinea pig, minipig or dog) at interval with certain dosage (can obtain to treat effective vivo concentration dosage, or preferred 0.01,0.05,0.1,0.5,1,5,10,40 or 50 mg/kg drug administration by injection or oral administration dosage).When continuous 5 days of administration every day or preferred 10 days, this kind dosage can not cause the liver enlargement yet, the result causes liver that the liver of the coupling matched group of the ratio laboratory Rodents (for example mice or rat) of body weight is increased the ratio of body weight and surpasses 100%, preferably is no more than 75% and more preferably no more than 50%.This kind dosage preferably can not cause hepatomegaly yet, result and dog or the mammiferous coupling of other non-Rodents and undressed matched group is compared, and liver increases by 50% to weight ratio, preferably is no more than 25% and more preferably no more than 10%.
Preferred compound can not facilitated in vivo yet and discharges liver ferment (for example ALT, LDH or AST) substantially by hepatocyte.Preferred aforementioned dosage is compared with the live test of the undressed matched group of coupling of laboratory Rodents, and the ferment serum-concentration that can not raise surpasses 100%, preferably is no more than 75% and reaches more preferably no more than 50%.In like manner, equal minimum in vivo treat 2 times of concentration, preferred 5 times and most preferably 10 times of concentration (culture medium or other test tube test exposing cell or with the solution of cell co-cultivation) can not cause in the test tube test, but any liver ferment is released into culture medium by hepatocyte with detection mode, is higher than the datum line concentration of the culture medium that derives from unprocessed cell.
Preferred compound does not have the remarkable activity as Na-ion channel blocker in addition, when existing with 4 μ M or following concentration, have sodium ion specificity ligand (for example batrachotoxin, Fugu ocellatus toxin or saxitoxin) and be lower than 15%, and more preferably suppress to be lower than 10% in conjunction with inhibitory action.It is that industry is well-known that sodium channel specificity ligand is analyzed in conjunction with calibrating.In addition, preferred compound does not have remarkable androgen antagonist activities (for example live test adopts the Hershberger calibrating to analyze, or people (2001) toxicology 163 (1) such as Nellemann are for example adopted in the test tube test: the described calibrating analysis of 29-38).Preferred compound is when existing with 4 μ M or following concentration, and the activation inhibitory action of analyzing the androgen receptor in test tube test calibrating is lower than 15%, more preferably less than 10% inhibitory action, and most preferably is lower than 5% inhibitory action.Remarkable activity one vocabulary shows that the change of result and matched group is the degree in p＜0.1 when using the canonical parameter calibrating with statistical significance to analyze for example student T test determination, or more preferably in the degree of p＜0.05.
For testing goal, as hereinafter going through, chemical compound provided herein can add isotopic labeling or add radioactive label.So the chemical compound of formula I citation can have one or more atoms to be substituted by the identical element atom, and described atom has atomic weight or mass number different atomic weight or the mass number common with nature.Can existing in herein, the isotope of chemical compound for example for example comprises hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine isotope 2H, 3H, 11C, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F reaches 36Cl.In addition, for example replace deuterium (promptly with heavy isotope 2H) can provide the metabolic stability degree higher treatment advantage, for example in vivo the half-life increases or the attenuating of dosage demand, is preferred in some cases therefore.
The preparation of VR1 regulator
The quinazoline that is substituted-4-ylamine analogues can use the preparation of standard synthetic method usually.Usually starting material can derive from the supplier for example west leather Ma Yali chat (Sigma-Aldrich) company (Saint Louis, Montana State), or starting material can get predecessor by commerce and uses existing plan synthetic.Speech for example can use the route of synthesis shown in arbitrary figure of similar response diagram 1-23, together with the known synthetic method of Synthetic Organic Chemistry circle, or as is familiar with the changing method of skill personage understanding." R " in the following response diagram represents that any meets the group of chemical compound explanation described herein.
" catalyst " vocabulary for example shows suitable transition-metal catalyst in the following response diagram, but unrestricted in, tetrakis triphenylphosphine palladium (O) or acid chloride (II).In addition, catalysis system for example comprises ligand, but unrestricted in, 2-(dicyclohexyl phosphino-) biphenyl and two-tert-butyl benzene also comprise alkali for example phosphoric acid, sodium carbonate or uncle's fourth sodium oxide or uncle's fourth potassium oxide.Transition-metal catalysis temperature or elevated temperature around uses multiple atent solvent to carry out, and atent solvent comprises, but non-limiting in, toluene, dioxane, DMF, N-methylpyrrole pyridine ketone, glycol dimethyl ether, diethylene glycol dimethyl ether and acetonitrile.When using in conjunction with proper metal-aryl-response agent, transition metal-catalyzed (mixing) aryl-aryl coupled reaction can be used to prepare the chemical compound that formula formula 1C, 2A and 2F, 3C, 5A and 5H, 14C, 15A, 16D, 18D, 19C, 20C and 22C are contained.Paired reactant/catalyst commonly used comprises aryl dihydroxy boric acid/palladium (O) (suzuki reaction; Miyaura and Suzuki (1995) chemistry is combined opinion 95:2459) and aryl trialkyl stannane/palladium (O) (Stille reaction; T.N.Mitchell, synthetic (1992) 803), aryl zinc/palladium (O) and the upright Asia/nickel (II) of aryl leather.
" reduction " vocabulary shows the process with nitro functions reduction becoming amido functional group.This kind changes shape and can adopt the well-known multiple mode of organic synthesis industry to carry out, comprise, but unrestricted in, catalytic hydrogenation, use the stannum dichloride reduction and use the titanous chloride. reduction.Comprehensive opinion reference: the Hudlicky of relevant method of reducing, the single chapter 188 of M. (1996) organic chemistry reduction ACS.
" activation " vocabulary shows synthetic conversion, and wherein the carbonyl of amide moieties is changed into suitable leaving group (L).This kind conversion for example can be used for preparing the chemical compound as formula formula 1F, 2E, 2G, 5F, 11A, 14I, 15G, 16L, 17H, 19I, 20I, 21C and 23H.The reactant that is suitable for carrying out this kind conversion is that the organic synthesis people in the industry is well-known, comprises, but unrestricted in, SOCl 2, POCl 3And fluoroform sulphur acid anhydride.
" oxidation " vocabulary shows synthetic conversion, and wherein methyl is changed into carboxylic acid functional.This kind conversion for example can be used for preparing chemical compound such as 10E, 11-C, 14E, 19E and 22D.The number of chemical agent that the organic synthesis people in the industry knows can be used to carry out this kind conversion, comprises, but unrestricted in, the KMnO in alkaline medium (as sodium hydroxide solution or aqueous pyridine) 4And the K in acid medium (as sulphuric acid) 2Cr 2O 7
" cyclisation " vocabulary shows synthetic conversion, and wherein neighbour-amino-benzoic acid, neighbour-amino-benzoate and neighbour-amino-benzonitrile are converted into corresponding 3H-quinazoline-4-one.The method of carrying out neighbour-amino-benzonitrile cyclisation comprises, but unrestricted in, react with the backflow formic acid that contains sodium acetate.The method of carrying out neighbour-amino-benzoic acid cyclisation comprises, but is not restricted to, with Methanamide reaction under heating up, or with formamidine acetate at inert solvent reaction, this reaction also is at high temperature to carry out.The method of carrying out neighbour-amino-benzoate cyclisation comprises, but is not restricted to, and at high temperature reacts in atent solvent with formamidine acetate.
In response diagram 8, " H 2N-Prot " amido functional group such as the 4-methoxy-benzyl amine of expression through protecting, and " deprotection " expression can be removed the chemical method of this kind protecting group by this method.The guard method that relevant organic synthesis people in the industry uses and the comprehensive opinion of deprotection method can reference: Greene, T. and Wuts, P. organic synthesis protecting group, the 3rd edition, John's power father and son company, 1999.
In the middle response diagram 9, " nucleophilic group " vocabulary shows primary amine or secondary level amine or alkoxide.
In reaction Figure 19, " deprotection " vocabulary shows that the C-O key of the whole bag of tricks cracking benzyl oxide that use organic synthesis people in the industry is familiar with obtains method of " deprotection " alcohol.This kind method is illustrated in reaction Figure 19, and the chemical compound of its formula of such as 19I can be converted to the deprotection alcohol as general formula 19J.The method of carrying out this kind conversion comprises, but is not restricted to, and uses hydrogen and suitable antigravity system such as palladium/carbon or Buddhist nun's Ruan nickel to carry out hydrogenolysis.The guard method that relevant organic synthesis people in the industry uses and the comprehensive opinion of deprotection method can reference: Greene, T. and Wuts, P. organic synthesis protecting group, the 3rd edition, John's power father and son company, 1999.
" demethyl " vocabulary shows the Me-O key of decomposition of methyl ether functional group, converts 16E to as 16D.The several different methods that this kind conversion can the organic synthesis people in the industry be known is carried out, and these methods comprise, but is not restricted to, and uses hydrobromic acid to handle, and uses lewis acid/nucleophilic group combined treatment, TMS iodine etc.
Response diagram 1
Response diagram 2
Response diagram 3
Figure A0380245201171
Response diagram 4
Response diagram 5
Figure A0380245201181
Response diagram 6
Response diagram 8
Response diagram 9
Reaction Figure 10
Figure A0380245201201
Reaction Figure 11
Reaction Figure 12
Reaction Figure 13
Reaction Figure 14
Figure A0380245201221
Reaction Figure 15
Figure A0380245201222
Reaction Figure 16
Reaction Figure 17
Reaction Figure 18
Figure A0380245201242
Reaction Figure 19
Reaction Figure 20
Figure A0380245201261
Reaction Figure 21
Figure A0380245201262
Reaction Figure 22
Reaction Figure 23
In some specific embodiment, the VR1 regulator contains one or more asymmetric c atom, so chemical compound can be different stereoisomeric forms in any ratio existence.These forms for example can be racemic form or optically-active form.As described above, all stereoisomer is all contained by the present invention.Though single enantiomer (being the optically-active form) so, wished to obtain in speech.The standard method for preparing single enantiomer comprises the optical segmentation method of asymmetric synthetic method and racemic mixture.The optical segmentation of racemic mixture for example can be reached by conventional method, for example crystallization in the presence of the optical segmentation agent, or use and for example chirality HPLC tubing string is carried out tomography.
As previously mentioned, the pharmaceutically acceptable salt of chemical compound described herein is contained in the present invention." the pharmaceutically acceptable salt " that is used for herein is acid salt or basic salt, and it is considered as being fit to contact tissue or animal body tissue by industry usually, and no mistake in treatment high toxicity, zest, anaphylaxis or other problem or complication.These salt comprise inorganic acid salt and organic acid salt of alkaline residue such as amine and/or alkali metal or alkaline-earth metal; Or the organic salt of acidic residues such as carboxylic acid.Specific pharmaceutical salts comprises, but be not restricted to, the salt that is generated with following acid, for example hydrochloric acid, phosphoric acid, hydrobromic acid, malic acid, glycolic, fumaric acid, sulphuric acid, sulfamic acid, phenyl-sulfamic acid, formic acid, toluenesulfonic acid, Loprazolam, benzenesulfonic acid, ethane disulfonic acid, 2-hydroxyethyl sulfonic acid, nitric acid, benzoic acid, the 2-acetoxy-benzoic acid, citric acid, tartaric acid, lactic acid, stearic acid, salicylic acid, glutamic acid, ascorbic acid, pamoic acid, succinic acid, fumaric acid, maleic acid, propanoic acid, hydroxy-maleic acid, hydroiodic acid, phenylacetic acid, alkyl acid such as acetic acid, HOOC-(CH 2) n-COOH is n=0-4 etc. herein.In like manner, pharmaceutically acceptable cation comprises, but is not restricted to, sodium, potassium, calcium, aluminum, lithium, and ammonium.Those skilled in the art answer a step to recognize other pharmaceutically acceptable salt of chemical compound described herein, comprise being set forth in 1418 pages of the 17th edition Binzhou Yi Shidun of Merck publishing company of Remington's Pharmaceutical Science (1985).Therefore, the disclosure must be interpreted as all pharmaceutically acceptable salt of the chemical compound that comprises special citation.
Multiple widely synthesis program can be used for preparing pharmaceutically acceptable salt.Usually, pharmaceutically acceptable salt can be synthetic by any conventional chemical method of parental generation chemical compound mat that contains basic moiety or acidic moiety.In brief, this kind salt can be via the suitable alkali of the free state acidity of these chemical compounds or alkaline form and stoichiometric amount or acid at water or in organic solvent, or in the mixture of the two prepared in reaction; Usually be preferred with non-aqueous media such as ether, ethyl acetate, ethanol, isopropyl alcohol or acetonitrile.
The prodrug of chemical compound provided herein can be via carrying out modification to the functional group that exists in the chemical compound, so modification partly is cracked into to parent compound and prepares.Prodrug comprises following chemical compound, and wherein hydroxyl, amino or sulfydryl key are connected to any group, and this chemical compound is when giving mammalian body, and is cleaved and generate free state hydroxyl, amino or sulfydryl respectively.Prodrug for example comprises, but the alcohol functional group of the chemical compound that provides herein and the acetate of amine functional group, formates and benzoate derivant is provided.The preferred precursor medicine comprises acylated derivatives.It will be understood by a person skilled in the art that the prodrug that can adopt several different methods to prepare chemical compound provided herein.
Chemical compound can synthesize via the precursor that use comprises at least one radiosiotope atom and add radio-labeled.Each radiosiotope be preferably carbon (as 14C), hydrogen (for example 3H), sulfur (for example 35S) or iodine (for example 125I).Tritiated compound also can prepare by exchanging or use chemical compound to allow some chemical compound accept tritium gas as substrate through the catalytic exchange of platinum, in tritiate trifluoroacetic acid mat acid catalysis at tritiate acetic acid.In addition, some precursors can optionally use tritium gas to carry out tritium-halogen exchange, tritium gas reduction unsaturated bond, or use boron tritiate sodium reduction.The preparation of radio-labelled compound can be synthesized by the radiosiotope supplier by the customized synthetic regulation of radiolabeled probe's chemical compound easily.
Medical composition
The present invention also provides and comprises one or more VR1 regulator, together with the medical composition of acceptable supporting agent of at least a physiology or excipient.Medical composition for example comprises one or more in water, buffer (for example neutral buffered saline solution or phosphate-buffered saline solution), ethanol, mineral oil, vegetable oil, dimethyl sulfoxine, carbohydrate (for example glucose, mannose, sucrose or glucosan), mannitol, protein, adjuvant, polypeptide or aminoacid such as glycine, antioxidant, chelating agen such as EDTA or glutathion and/or the preserving agent.As described above, other active component can (but inessential) include in medical composition provided herein.
Adjustable any the suitable administering mode that is used for of medical composition for example comprises topical, oral administration, nose administration, per rectum administration or through the intestinal external administration.The outer speech of intestinal is used for herein, and comprise subcutaneous injection, intradermal injection, intravascular injection (for example intravenous injection), intramuscular injection, vertebra injection, intracranial injection, intrathecal injection, reach injection in the abdomen, and any similar injection or infusion techniques.In some specific embodiment, serve as preferred to be suitable oral compositions.These dosage forms for example comprise tablet, buccal tablet, lozenge, aqueous or oily suspensions agent, can disperse powder or granule, emulsion agent, hard capsule or soft capsule or syrup or elixir.In another specific embodiment again, the present composition can be formulated into lyophilized formulations.Topical is used for some disease with blender and is preferred (for example treat dermatosis, as burn and scald or scratch where it itches).
Oral administration further comprises one or more composition for example sweeting agent, flavoring agent, coloring agent and/or preserving agent with compositions, so that tempting and good to eat preparation to be provided.Tablet contains active component and is mixed with the acceptable excipient that is suitable for making tablet of physiology.This kind excipient for example comprises inert diluent (as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate), granulating agent and disintegrating agent (as corn starch or alginic acid), binding agent (as starch, gelatin or arabic gum) and lubricant (as magnesium stearate, stearic acid or Talcum).Tablet is coating not, or tablet can be by the known technology coating, and postponing provides long-time continuous action thus in gastrointestinal disintegrate and absorption.For example the up time postpones material such as glyceryl monostearate or distearin.
Blender for oral use also can be the hard-gelatin capsules dosage form, wherein active component is mixed with inert solid diluent (as calcium carbonate, calcium phosphate or Kaolin) or is Gelseal, and wherein active component has mixed aqueous medium or oily medium (for example Oleum Arachidis hypogaeae semen, liquid paraffin or olive oil).
The aqueous suspension liquor contains active component and has mixed the excipient that is suitable for making the aqueous suspension liquor.This kind excipient comprises suspending agent (as sodium carboxymethyl cellulose, methylcellulose, hydroxy propyl cellulose, sodium alginate, pyrollidone, tragakanta and arabic gum); And dispersant or wetting agent (for example the condensation product of natural phospholipid such as lecithin, alkylene oxide and fatty acid such as polyoxy are stretched the condensation product of ethyl stearate, oxirane and long-chain fatty alcohol such as heptadecane ethyl oxygen base spermol, oxirane and derived from the condensation product of the part ester of fatty acid and hexitol, as polyoxy stretch ethyl Sorbitol monooleate or oxirane and derived from the condensation product of fatty acid and hexitan part ester, for example poly-poly-Sorbitol monooleate of ethyl of stretching).The aqueous suspension liquor also comprises one or more preserving agent, and for example ethylparaben or P-hydroxybenzoic acid n-propyl, one or more coloring agent, one or more flavoring agent reach one or more sweeting agent for example sucrose or glucide.
The oily suspensions agent can be via active component being suspended in vegetable oil (as Oleum Arachidis hypogaeae semen, olive oil, Oleum sesami or Oleum Cocois) or being suspended in mineral oil such as liquid paraffin and allocating.The oily suspensions agent contains thickening agent such as Cera Flava, hard paraffin or spermol.Can add for example aforementioned sweeting agent and/or flavoring agent good to eat oral formulations is provided.This kind suspension liquor can be by adding antioxidant such as ascorbic acid preservation.
Be fit to comprise active component mixed dispersant or wetting agent, suspending agent and one or more preserving agent by adding disperseed powder and the granule that water prepares the aqueous suspension liquor.Suitable dispersant or wetting agent and suspending agent are to illustrate as described above.Also can have other composition such as sweeting agent, flavoring agent, reach coloring agent.
Medical composition also can be the emulsion oil-in-water agent.Oil phase can be vegetable oil (as olive oil or Oleum Arachidis hypogaeae semen, mineral oil such as liquid paraffin or its mixture).Suitable emulsifying agent comprises natural plastics (as arabic gum or tragakanta), natural phospholipid (as Semen sojae atricolor, lecithin, reaching ester or part ester derived from fatty acid and hexitol), anhydride (as poly-Sorbitol monooleate), reaches derived from the part ester of fatty acid and hexitol and the condensation product of oxirane (stretching the poly-Sorbitol monooleate of ethyl as polyoxy).Emulsion also comprises one or more sweeting agent and/or flavoring agent.
Syrup and elixir can use the sweeting agent allotment, and sweeting agent for example is glycerol, propylene glycol, Sorbitol or sucrose.These blenders also comprise one or more demulcent, preserving agent, flavoring agent and/or coloring agent.
The used blender of topical typically comprises local with mediator combined activity composition, contains or do not contain additionally randomly composition.Suitable part is that industry is well-known with mediator and other composition, and obviously the selection of mediator will be according to specific physical form and transport model decision.Local mediator comprises water; Organic solvent is as alcohol (as ethanol or isopropyl alcohol or glycerol); Glycol (as butanediol, isoamyl glycol or propylene glycol); Aliphatic alcohol (as lanoline); The mixture of water and organic solvent, and ORGANIC SOLVENT MIXTURES such as alcohol and glycerol mixture; Based on the material of lipid such as fatty acid, acylglycerol (fat that comprises oil as mineral oil and natural origin or synthetic source), phosphoglycerol esters, sphingomyelins, reach wax; Material such as collagen and gelatin based on protein; Material (comprising non-volatile and volatility) based on poly-silica; And based on material such as the microsponge and the polymeric matrix of hydrocarbon.Compositions comprises that further one or more is fit to the composition that the stability or the effect of blender are used in improvement, for example tranquilizer, suspending agent, emulsifying agent, viscosity modifier, gellant, preserving agent, antioxidant, dermal osmosis accelerator, wetting agent, and continue releasable material.These compositions are for example stated at extra pharmacopeia of Martindale--(pharmacy publishing house London 1993) and Martin (editor) Remington's Pharmaceutical Science.Composite can comprise microcapsule such as hydroxy-methyl cellulose or gelatin microcapsule, liposome, albumin microsphere, microemulsion, nanoparticle or Nano capsule.
Local composite can be prepared into multiple physical form and for example comprise solid preparation, paste agent, ointment, foaming agent, lotion, gel, powder, aqueous liquor, reaches emulsion agent.The solid appearance of these dosage forms and viscosity are by whether having the decision of emulsifying agent and viscosity modifier and amount thereof in the composite.Solid preparation is normally solid and not dumpable, normally is deployed into shaft-like or bar-shaped or is deployed into the granule dosage form; Solid preparation can be opaque or transparent, randomly contains solvent, emulsifying agent, wetting agent, lubricant, spice, dyestuff/coloring agent, preserving agent, and other can increase or promote the active component of end-product effect.Ointment and lotion are often similar each other, mainly have only viscosity differences; Lotion and ointment can be opaque, translucent or transparent, often contain emulsifying agent solvent and viscosity modifier and wetting agent, lubricant, spice, dyestuff/coloring agent, preserving agent, and other can improve or strengthen the active component of end-product effect.Gel can be prepared into broad range of viscosities, by stiff or high viscosity to thin or low viscosity.Similar lotion of these composites and ointment also contain solvent, emulsifying agent, wetting agent, lubricant, spice, dyestuff/coloring agent, preserving agent, and other can improve or strengthen the active component of end-product effect.Liquor is thinner than ointment, lotion or gel, does not often contain emulsifying agent.The liquid topical formulations often contains solvent, emulsifying agent, wetting agent, lubricant, spice, dyestuff/coloring agent, preserving agent, and other can improve or strengthen the active component of end-product effect.
The suitable emulsifying agent that uses for local composite comprises, but be not restricted to, ionic emulsifier, spermol, non-ionic emulsifier such as polyoxy are stretched ethyl oleyl ether, PEG-40 stearic acid, ceteareth-12, ceteareth-20, ceteareth-30, ceteareth alcohol, PEG-100 stearic acid and tristerin.Suitable viscosity modifier comprises, but is not restricted to, and protecting colloid or nonionic natural gum as hydroxyethyl-cellulose, HUANGJIAO, almasilate, silica, microwax, Cera Flava, paraffin, reaches cetin.Gel combination can generate by adding gellant, and gellant is carapace polysaccharide, methylcellulose, ethyl cellulose, polyvinyl alcohol, polyquaterniums, hydroxy ethyl cellulose, hydroxy propyl cellulose, HYDROXY PROPYL METHYLCELLULOSE, carbomer (carbomer) or ammonification glycyrrhetate for example.Suitably interfacial agent comprises (but non-limit exists) non-ionic surfactant, amphion interfacial agent, ionic interfacial agent, reaches the anionic property interfacial agent.For example the part can use one or more dimethicone polyol, polysorbate20, polysorbate40, polysorbate60, polysorbate80, lauramide DEA, cocoamide DEA and cocoamide MEA, oil base dish alkali, cocoamide propyl group phospholipid base PG-dimonium chloride, reach the lauryl sulfate ammonium with composite.Suitably preserving agent comprises, but non-being limited to, antimicrobial such as methyl parahydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid, benzoic acid, and formaldehyde, and physics tranquilizer and antioxidant such as the plain E of little life, sodium ascorbate/ascorbic acid and propyl gallate.Suitably wetting agent comprises (but non-being limited to) lactic acid and other hydroxy acid and its esters, glycerol, propylene glycol, reaches butanediol.The proper lubrication agent comprises lanolin alcohol, lanoline, lanolin derivative, cholesterol, soft paraffin, the different stearyl ester of neopentanoic acid, reaches mineral oil.Suitably spice and colorant comprise (but non-being limited to) FD﹠amp; C red No. 40 and FD﹠amp; Yellow No. 5 of C.Other proper composition that local composite can include comprises that (but non-being limited to) abradant, absorbent, anticaking agent, defoamer, antistatic additive, astringent (for example Radix Hamamelidis Mollis, ethanol and crude drug extract such as Flos Chrysanthemi extract), tacky adhesive/excipient, buffer agent, chelating agen, thin film generate agent, conditioner, propellant, opacifying agent, pH regulator agent, reach protective agent.
The suitable local mediator that the allotment gel is used for example is: hydroxy propyl cellulose (2.1%); 70/30 isopropanol (90.9%); Propylene glycol (5.1%); And polysorbate80 (1.9%).The suitable part that the foaming agent composite is used for example is spermol (1.1%) with mediator; Stearyl alcohol (0.5%); Quaternium52 (1.0%); Propylene glycol (2.0%); Alcohol 95 PGF3 (61.05%); Deionized water (30.05%); P75 hydrocarbon propellant (4.30%).All percentages is by weight.
The transport model of typical topical composition comprises using to point to be used; Use the physics applicator to use, the physics applicator for example is cloth, facial tissue, swab, rod or brush; Spraying (comprising mist, aerosol or foaming spraying); Drop is used; Spill and use; Soak and cleaning.Also can use the sustained release mediator.
Medical composition can be prepared into aseptic injection aqueous suspension or oily suspensions.Decide according to the mediator that uses and concentration, regulator can be suspended in or be dissolved in mediator.This kind compositions can use that suitable dispersant, wetting agent and/or suspending agent are for example aforementioned to be allocated according to known technology.Useful acceptable mediator and solvent comprise water, 1,3 butylene glycol, Ringer's mixture and isotonic sodium chlorrde solution.In addition, can use aseptic fixedly oil as solvent or suspension media.For reaching this purpose, can adopt the fixedly oil of any brand, comprise a synthetic acid glyceride and synthetic Diglyceride.Can be used for preparing composition for injection as fatty acids such as oleic acid in addition, may be dissolved in mediator as adjuvant such as local anesthetic, preserving agent and/or buffer agent.
Regulator also can be prepared into suppository formulation (for example using for rectally).The method for making of this kind compositions can mix and prepare with suitable non-irritating excipient via medicine, and this excipient is a solid at room temperature, but is liquid in the anus temperature, therefore discharges medicine in the rectum fusion.Suitable vehicle for example comprises cocoa butter and Polyethylene Glycol.
Medical composition can be formulated into and continue to discharge composite (be composite such as capsule its slowly release regulator after administration).This kind composite can use the preparation of well-known technology, and for example oral, per rectum or subcutaneous implantation give or implant assigned target position.The supporting agent that this kind composite uses as biology compatible also can be biological decomposable; Preferred composite can provide the regulator emission levels of quite stable.The regulator content that continues to discharge in the composite is according to implant site, estimates that rate of release and release time and desire are treated or the disease character decision of desire prevention.
Additionally or together with aforementioned mode of administration, regulator can add food or drinking-water [for example give the non-human animal and comprise companion animals (as dog and cat) and animals] easily.Animal feed and drinking-water compositions can be formulated into animal and can take an amount of compositions together with diet.Also can easily compositions be provided as the premixing agent for being added into feedstuff or drinking-water.
Regulator is normally with the administration of capsaicin receptor regulated quantity [can reach enough inhibition class vanilloid ligands seat is bonded to the VR1 desired concn in the test tube test consumption in body fluid (as blood, blood plasma, serum, CSF, synovial fluid, lymph, interstitial cell fluid, tear or urine)].When used dosage can obtain distinguishable patient's effect for example as described here during pain relief, this dosage is regarded as treating effective dose.The optimum decision system dosage is not higher than 50 milligrams of per kg body weight per day (for example in about 0.001 milligram of scope to about 50 mg/kg body weight/day), and oral dose is usually than high about 5-20 times (for example in 0.01 scope to 40 mg/kg/body weight) of vein dosage.
Can combine the active component consumption of making single dosage form with carrier materials will be according to the patient who for example receives treatment and specific administration pattern and change.Unit dosage forms contains 10 micrograms of having an appointment usually to about 500 milligrams of active component.Most preferred dose can use routine test to determine that routine testing program is that industry is well-known.
Medical composition can be packed to be used for treating VR1 is regulated the disease that responds (for example treatment is exposed to class vanilloid ligand seat, pain, scratches where it itches, fat or urinary incontinence).Medical composition through packing can comprise at least a regulator of VR1 as described here for the treatment of effective dose with the container splendid attire, and indicates contained compositions will be used for treating patient's the disease to responding property of VR1 adjusting with instruction (for example label).
Using method
VR1 regulator provided herein can be used as the capsaicin receptor comprises test tube test and live test in many-side agonist or (preferably) antagonist.In some aspects, the VR1 antagonist can be used at test tube or in vivo suppresses class vanilloid ligand seat agonist (for example capsaicin and/or RTX) be bonded to the capsaicin receptor.Usually this kind method is included in the existence of class vanilloid ligand seat down, in aqueous solution and under the suitable condition of ligand in conjunction with the capsaicin receptor, and the step of one or more quinazolines-4-ylamine analogues of capsaicin receptor contact capacity.The capsaicin receptor can be present in solution or suspension (for example in isolated cells film or cell preparation) or be present in cultured cell or isolated cells.In some specific embodiment, the capsaicin receptor is that aqueous solution is a body fluid by patient's neuronal cell performance.Usually, the quantity of the quinazoline that contacts with receptor-4-ylamine analogues will obtain enough to suppress the concentration of class vanilloid ligand seat in conjunction with VR1 in vitro at aqueous solution, for example use embodiment 5 described combination calibrating analyses and/or embodiment 6 described calcium to move the calibrating assay determination.Preferred one or more quinazoline-4-ylamine analogues is to be 100nM or following at least a body fluid of animal with treatment valid density with analog, preferred 50nM or following, and 20nM or following, or 10nM or following quantity give animal.For example chemical compound can be lower than 20 mg/kg body weight, preferably is lower than the dosed administration that is lower than 1 mg/kg under 5 mg/kg and some situation.
The active method of signal transduction that suppresses the capsaicin receptor that is preferably of regulating also is provided herein.This kind adjusting can be via capsaicin receptor (in vitro or in vivo) under the condition that is fit to the regulator bind receptor, and one or more VR1 regulators provided herein of contact effective dose are reached adjusting.Receptor can be present in solution or the suspension, is present in cultured cell preparation or the isolated cells preparation, or is present in patient's body.The active adjusting of signal transduction can be appraised through comparison by the effect that detects calcium ion conduction (be also referred to as and be calcium mobility or calcium flux).Usually, effective dose VR1 regulator is enough to obtain in the test tube test as embodiment 6 described calcium move calibrating and analyze, obtain the enough active concentration of adjusting VR1 signal transduction (with aqueous solution that receptor contacts in).VR1 regulator provided herein is preferably oral or through topical administration patient (for example human), and is present at least a body fluid inside of animal body, regulates VR1 signal transduction activity simultaneously.The VR1 regulator that is preferred for this kind method can 1nM or following, preferred 100pM or following, more preferably 20pM or following transduction activity of regulating the VR1 signal in vitro; And the transduction activity of in body fluid such as blood, regulating the VR1 signal in vivo with 100nM or following concentration.
The present invention further provides treatment and VR1 is regulated the method for the disease of responding property.In content of the present invention, disease modification processing contained in " processing " speech and symptom is handled, two kinds of processing all can be and preventatively (promptly begin pre-treatment in symptom, to prevent, to postpone or reduce the order of severity of symptom) or therapeutic (promptly beginning post processing in symptom, to reduce severity of symptom and/or duration of symptoms).A kind of disease is if to it is characterized by the capsaicin receptor active undesired, and the class vanilloid ligand seat quantity that exists with the part is irrelevant, and/or regulates the capsaicin receptor active and can obtain alleviating of the state of an illness or symptom, and then this kind disease " is regulated responding property to VR1 ".These diseases comprise for example be exposed to VR1 activation stimulate the symptom that causes, pain, respiratory symptom for example asthma and Chronic obstructive pulmonary disease, scratch where it itches, urinary incontinence, cough, have the hiccups, and fat, be detailed later.These diseases can use the set standard of industry to diagnose and monitor.The patient comprises the mankind, family's companion animals and domestic animal, and its dosage is as the preamble explanation.
The usage and dosage of treatment is to change according to the specific condition of using the treatment of chemical compound and desire.But being used for the treatment of most of disease, serves as preferred below 4 times or 4 times with administration every day.Usually with every day twice usage and dosage for more preferably, with administration once a day for most preferably.For management of acute pain, wish that single agent medication can reach valid density fast.But given dose and the particular treatment plan that must understand particular patient will be according to multinomial factors, the specified disease order of severity decision that comprises specific compound activity, age, body weight, general health situation, sex, diet, administration time, route of administration and discharge rate, the drug regimen of employing and receive treatment.Usually it serves as preferred enough providing the minimum dose of effective treatment with use.The patient preferably uses the state of an illness that is suitable for receiving treatment or accepts to prevent medical standard or veterinary's standard of the state of an illness to monitor curative effect.
The patient who symptom occurs owing to the stimulation that is exposed to the capsaicin receptor activation comprises the patient who causes burn and scald because of heat, light, teargas or acid, and mucosa (for example by eating, suck or the eye contact) is exposed to capsaicin (for example from the capsaicin of Fructus Capsici or the capsaicin of pepper spray agent) or related stimulus agent for example acid, teargas and air-polluting individuality.The symptom that causes (can use the symptom of compounds for treating provided herein) for example comprises pain, bronchus constriction, and inflammation.
Can use the pain of compounds for treating provided herein to can be chronic or acute pain, comprise but unrestricted disease (being in particular neuropathy degeneration pain) in the neural media of periphery.Chemical compound provided herein for example can be used for treating mastectomy postoperative pain syndrome, stump pain, phantom limb pain, oral cavity neuropathy pain, toothache (toothache), phantom tooth pain, postherpetic neuralgia, diabetic neuropathy, reflection sympathetic nerve nutritional disorder, trigeminal neuralgia, osteoarthritis, rheumatoid arthritis, fibromyalgia, returns-Bai two Cotards, Bernhards disease, calcination-oral cavity syndrome and/or two side periphery neuropathy.Other neuropathy degeneration pain comprises causalgia (reflection sympathetic nerve nutritional disorder-RSD, be secondary to after the peripheral injured nerve), the neuritis (comprises for example sciatic neuritis, the periphery neuritis, polyneuritis, optic neuritis, fever back neuritis, animal migration neuritis, the segmenting neuritis, and tribute Bo Shi neuritis), celluloneuritis, neuralgia (for example aforementioned neuralgia, cervico-brachial neuralgia, the skull neuralgia, the knee joint neuralgia, tongue and laryngeal nerve pain, migrainous neuralgia, idiopathic neuralgia, intercostal neuralgia, mammary neuralgia, the jaw Joint neuralgia, Tong Shi neuralgia not, the nervi nasociliaris pain, occipital neuralgia, erythromelalgia, sluder's neuralgia, spleen jaw neuralgia, eye socket epineural pain and nervus canalis pterygoidei pain), it is ache related to perform the operation, musculoskeletal pain, acquired immune deficiency syndrome (AIDS) related neural pathological changes, MS-related neural pathological changes, and vertebrae injry is ache related.Headache comprises pain for example hole, bunch (for example migrainous neuralgia) that involves peripheral neural activity, and some tension pressures and pain and migraine also can be treated as described here.In case for example the patient feels to have the migraine omen, give chemical compound provided herein at once and come prevention of migraine.Other the pain state of an illness that can treat as described here comprises " calcination oral cavity syndrome ", pain of childbirth, summer Ke Shi pain, intestinal tympanites pain, dysmenorrhoea, acute and chronic backache, hemorrhoid pain, dyspepsia pain, angina pectoris, radiculalgia, co-located pain, reaches the diverse location pain, comprise the pain (for example osteocarcinoma patient's pain) that cancer causes, the pain (with inflammation) that snake venom (for example venom, spider bites or insect bite) causes, and the pain that causes of wound (for example postoperative pain, incised wound, injury with blood-stasis, and the fracture pain and the burn and scald pain that cause).Other the pain state of an illness that can treat as described here comprises inflammatory enteropathy, zest bowel syndrome and/or inflammatory enteropathy.
Aspect some, the VR1 antagonist comprises that (but non-being limited to) special VR1 antagonist of quoting from can be used for treating mechanicalness pain herein.Be used for " mechanicalness pain " vocabulary herein and show that pain beyond the headache, this pain are not neuropathy or owing to are exposed to heat, cold or result that outside chemical stimulation caused.Mechanicalness pain comprises physical trauma (hot burn and scald or chemicals burn or other zest exposes and/or painful is exposed to except the Harmful chemicals) for example postoperative pain and incised wound, blood stasis and fracture pain; Toothache, phantom tooth pain; Radiculalgia; The pain that osteoarthritis, rheumatoid arthritis, fibromyalgia, paraesthesia osteodynia, backache, cancer cause pain, angina pectoris, carpal tunnel syndrome and cause because of fracture, childbirth, hemorrhoid, intestinal tympanites, dyspepsia and menstruation.Any can Ki less than the VR1 antagonist of 100 μ M in conjunction with VR1, and/or can EC 50Being less than or equal to the active VR1 antagonist of 100 μ M (measuring as described here) inhibition VR1 all can use.The preferred VR1 antagonist that uses not is the capsaicin analog; Particularly preferred VR1 antagonist is an antagonist provided herein.
The medicable state of an illness of scratching where it itches comprises that chronic eczema scratches where it itches, washes that kidney causes scratches where it itches, malaria originality is scratched where it itches, and vaginal orifice inflammation, contact dermatitis, lnsect bite injure scratching where it itches that skin allergy causes.Urinary incontinence one speech is used for comprising the hyperfunction and irritable bladder of urgent muscular reflex in vertebra source herein, and the two all can be treated as described here.Chemical compound provided herein also can be used as antitussive (preventing, alleviate or suppress cough) and is used for the treatment of and has the hiccups, and the loss of weight that promotes the obese patient.The treatment effective dose of these methods enough provides the detectable alleviation of the disease for the treatment of usually.
In others, VR1 antagonist provided herein can be used for treating the disease that relates to the inflammation composition in combined therapy.These diseases comprise for example autoimmune disease and the known pathologic autoimmune disease that contains the inflammation composition, comprise, but be not restricted to the hyperacute rejection of arthritis (particularly rheumatoid arthritis), psoriasis, Crohn disease, lupus erythematosus, sharp hot-tempered property bowel syndrome, tissue grafts repulsion and transplant organ.Other disease comprises wound (for example head injuries or vertebrae injry), cardiovascular diseases and cerebrovascular and some inflammatory diseases.
For combined therapy, the VR1 antagonist is to give the patient together with antiinflammatory.VR1 antagonist and antiinflammatory can be present in the same medical composition, or can any order separate administration.Antiinflammatory comprises for example nonsteroid anti-inflammatory drugs (NSAIDs), non-specific-as to reach COX-2 (COX-2) specificity-cyclooxygenase-2 inhibitors, gold compound, corticosteroid, methotrexate, tumor necrosis factor (TNF) receptor antagonist, anti-TNF alpha antibody, resist-C5 antibody and Jie's white matter-1 (IL-1) receptor antagonist.NSAIDs for example comprises but non-the ibuprofen, (ADVIL for example of being limited to TM, MOTRIN TM), flurbiprofen (ANSAID TM), naproxen or naproxen sodium (for example NAPROSYN, ANAPROX, ALEVE TM), diclofenac (CATAFLAM for example TM, VOLTAREN TM), the combination of diclofenac sodium and Mi Suopusi appropriate (misoprostol) (ARTHROTEC for example TM), Shu Linsu (CLINORIL TM), Ou Sapuxin (oxaprozin) (DAYPRO TM), diflunisal (DOLOBID TM), piroxicam (FELDENE TM), indometacin (INDOCIN TM), etodolac (LODINE TM), Feprona, (NALFON TM), ketoprofen (ORUDIS for example TM, ORUVAIL TM), sodium Na Bumeitong (nabumetone) (RELAFEN TM), sulfasalazine (AZULFIDINE TM), tolmetin sodium (TOLECTIN TM) and hydroxychloroquine (pula quino (PLAQUENIL TM).A specific class NSAIDs comprises chemical compound Sai Lekaoxi (the celecoxib) (CELEBREX for example that can suppress cyclooxygenase (COX) TM) and Luo Feikaoxi (rofecoxib) (VIOXX TM).NSAIDs further comprises Salicylate for example acetylsalicylic acid or aspirin, sodium salicylate, choline salicylate and magnesium salicylate (TRILISATE TM) and salsalate (DISALCID TM) and corticosteroid cortisone (CORTONE for example TMAcetate), dexamethasone (DECADRON for example TM), methylprednisolone (MEDROL TM), prednisolone (PRELONE TM), prednisolone na phosphates (PEDIAPRED TM) and prednisone (PREDNICEN-M for example TM, DELTASONE TM, STERAPRED TM).
In this kind combined therapy, the suitable dosage of VR1 antagonist usually explanation as before.The dosage of antiinflammatory and medication for example can be with reference to manufacturer's indications of doctor's desktop handbook.In some specific embodiment, the combination medicine-feeding of VR1 antagonist and antiinflammatory can obtain to produce the reduction of the required antiinflammatory dosage of curative effect.Be the not combination that is lower than manufacturer recommendation when giving the VR1 antagonist so preferably at the antiinflammatory dosage of combination of the present invention or combination therapy of the present invention, the recommendation maximum dose level of antiinflammatory administration.More preferably this kind dosage with manufacturer recommendation during not with VR1 antagonist combination medicine-feeding the administration maximum dose level of antiinflammatory compare, be to be lower than 3/4 of this maximum dose level, even more preferably less than 1/2 and highly preferably be lower than 1/4, most preferably this dosage is to be lower than 10%.Obviously reach VR1 antagonist dose of components in the required combination of desired effects and be equally the antiinflammatory dose of components in being made up and the influence of antiinflammatory intensity.
In some preferred embodiments, VR1 antagonist and antiinflammatory combination medicine-feeding can be by being packaged in same packing with one or more VR1 antagonist and one or more antiinflammatory, or be packaged in the interior autonomous container of packing, or preferably be the mixture administration of one or more VR1 antagonist and one or more antiinflammatory.Preferred mixture is allotment (for example being pill, capsule, tablet etc.) for oral administration.There is label to indicate one or more VR1 antagonisies and one or more antiinflammatory co-administered to be used for treating the inflammation antalgesic in the preferred packaging.The height preferred compositions for antiinflammatory wherein comprise at least a COX-2 specificity cyclooxygenase-2 inhibitors for example Fan Dekaoxi (valdecoxib) (BEXTRA_), Rumi La Kaoxi (lumiracoxib) (PREXIGE TM), her appropriate Rui Kaoxi (etoricoxib) (ARCOXIA_), Sai Lekaoxi (CELEBREX TM) and/or Luo Feikaoxi (VIOXX_).
Preceding method adopts VR1 antagonist regulator usually; But also provide the method for the regulator that adopts the VR1 agonist herein.These regulators for example can be used for controlling mass movement (as the teargas succedaneum) be used for personnel protection (being used for spray) or as by capsaicin receptor desensitization treatment pain, scratch where it itches or the medicament of urinary incontinence.The chemical compound that is generally used for mass movement control or personnel protection is according to conventional teargas or allotment of pepper spray technology and use.
At different aspect, the test tube use or the live body that the invention provides multiple non-medicine are used for chemical compound provided herein.For example these chemical compounds can be labelled or are used to detect capsaicin receptor and capsaicin receptor mapping (in a corpse or other object for laboratory examination and chemical testing for example cell preparation or tissue slice, preparation or its part).Chemical compound also can be used for the receptor positive calibrating and analyzes as positive control, as the standard substance of measuring in conjunction with capsaicin receptor candidate agent ability, or as the radiation tracer of positron emission tomography art (PET) imaging, or as the radioactive tracer of single positron emission compute tomography (SPECT).This kind method can be used to determine the capsaicin acceptor property of live body.For example the VR1 regulator can use the well-known multinomial technical mark of industry (for example using radioactivity nuclear species described herein such as tritium to make radioactive label), and cultivates one section suitable incubation time (for example at first one section binding time mensuration is analyzed in calibrating) with a corpse or other object for laboratory examination and chemical testing.After the cultivation, remove (for example the mat washing is removed) unconjugated chemical compound, (for example radioactivity photography or scinticounting are used for radio-labelled compound automatically to use any method that is fit to this labelling to detect binding compounds; Spectrophotometric spectra art method is used to detect luminophore and fluorophor).As for contrast, contain through the coupling corpse or other object for laboratory examination and chemical testing of labelled compound and greater amount (for example 10 times a large amount of) un-marked chemical compound and can handle in the same manner.There is the greater amount detectable label to stay a test corpse or other object for laboratory examination and chemical testing than matched group, has the capsaicin receptor in the expression corpse or other object for laboratory examination and chemical testing.Detect the calibrating analysis and comprise that the capsaicin receptor can be as Kuhar in the popular scheme of pharmacology (1998) John's power father and son company in the automatic radioactivity photography of the receptor of cultured cell or tissue sample (receptor mapping), New York, 8.1.1 saves to described the carrying out of 8.1.9 joint.
Regulator provided herein also can be used for multiple widely well-known cell isolation method.For example regulator can be linked to tissue culturing plate or other support body inner surface, and regulator can be used as brakes capsaicin receptor thereby the peppery plain receptor of separating pepper (cell that for example separates expressed receptor) in vitro as affine ligand.In a preferred embodiment, be linked to the regulator exposing cell of fluorescent labeling such as fluorescein, (or separation) analyzed in mat fluorescein activating cell screening (FACS) then.
The following example is for illustrating and nonrestrictive.Unless make separate stipulations, otherwise total overall reaction thing and solvent belong to the normal business grade, without being further purified promptly for using.
Embodiment 1
The preparation of representative compounds
Present embodiment illustrates the preparation of the representational quinazoline that is substituted-4-ylamine analogues.This example reaches subsequently, and mass spectrometric data shown in each example is that EFI spills MS, be under positive ion mode, to use 15 volts of awl voltages, use trace (Micromass) flight time LCT, be equipped with Wa Teshi (Waters) 600 pumps, Wa Teshi 996 photodiode array detectors, gill gloomy (Gilson) 215 automatic samplers and gill gloomy 841 little infusion appliancees acquisition EFIs and spill MS.3.5 editions softwares of MassLynx (advanced chemical developer company, Toronto) are used for the collection and the analysis of data.1 microlitre volume sample injects 50 * 4.6 millimeters Chromolith SpeedROD C18 tubing strings, uses the elution of two-phase linear gradient with 6 ml/min flow velocitys.Sample uses full absorption ratio technology in 220-340 nano-ultraviolet light range detection.Elution requirement is mobile phase A-95/5/0.1 water/methanol/trifluoroacetic acid; Mobile phase B-5/95/0.05 water/methanol/trifluoroacetic acid.
Gradient time %B
0???????????????????????10
0.5?????????????????????100
1.2?????????????????????100
1.21????????????????????10
Total operation is injected to 2 minutes for being injected into running time.
A. (4-trifluoromethyl-phenyl)-[7-(2-trifluoromethyl-phenyl)-quinazoline-4-yl]-amine (chemical compound 1)
1. 3-nitro-2 '-trifluoromethyl-biphenyl-4-carboxylic acid methyl ester
Figure A0380245201411
At 2-(trifluoromethyl)-phenyl dihydroxy boric acid (4.4 grams, 0.0232 2-(dicyclohexyl phosphino-) biphenyl (111 milligrams, 0.318 mM) and potassium phosphate (6.52 grams mole),, 0.031 mM) add acid chloride (II) (36 milligrams, 0.160 mM) in the solution in toluene.Reactant mixture adds 4-chloro-2-nitrobenzoic acid methyl ester then with dried nitrogen purging 10 minutes.Reactant mixture is overnight 80 ℃ of following heated and stirred, and cooling mixture uses ethyl acetate to filter through C ore deposit (celite).Under reduced pressure concentrate, absorb in fresh ethyl, solution washs with sodium bicarbonate (saturated aqueous).Solution (sodium sulfate) under reduced pressure concentrates through dehydration, use then ethyl acetate as eluant through filtered through silica gel.Under reduced pressure remove solvent and obtain pure 3-nitro-2 '-trifluoromethyl-biphenyl-4-carboxylic acid methyl ester, be oil.
2. 3-amino-2 '-trifluoromethyl-biphenyl-4-carboxylic acid methyl ester
Figure A0380245201421
In handkerchief Er Shi device, use the alcoholic solution of tetrakis triphenylphosphine palladium (O) (300 milligrams) hydrogenation 3-nitro-2 '-trifluoromethyl-biphenyl-4-carboxylic acid methyl ester (5.54 grams, 0.0169 mole) under 55psi hydrogen.After 18 hours, mixture filters through the C ore deposit, under reduced pressure concentrates, and obtains 3-amino-2 '-trifluoromethyl-biphenyl-4-carboxylic acid methyl ester, is solid.
3. 7-(2-trifluoromethyl-phenyl)-3H-quinazoline-4-one
Figure A0380245201422
3-amino-2 '-trifluoromethyl-biphenyl-4-carboxylic acid methyl ester (5.0 gram, 0.0169 mole) and carbonamidine acetas (2.8 grams, 0.0203 mole) were the solution reflux of 2-methyl cellosolve 8 hours.Cooling mixture, decompression concentrates down, obtains dark oil.Residue is dissolved in 10% sodium hydroxide, with ether washing (3 times).Water layer uses 12N hydrochloric acid to be adjusted into pH to be about 4 and obtain milky solution.Solution uses ethyl acetate extraction, and ethyl acetate is washed with saline solution, and dehydration (sodium sulfate) and under reduced pressure concentrated 7-(2-trifluoromethyl-phenyl)-3H-quinazoline-4-one that obtains are the light brown solid.
4. 4-chloro-7-(2-trifluoromethyl-phenyl)-quinazoline
7-(2-trifluoromethyl-phenyl)-3H-quinazoline-4-one (1.12 grams, 0.0039 mole) is at POCl 3Solution in refluxed 16 hours.Cooling mixture and under reduced pressure concentrated.The residue branch is dissolved in saturated aqueous sodium bicarbonate and ethyl acetate.Ethyl acetate layer is washed once with sodium bicarbonate again, and dehydration (sodium sulfate) and the under reduced pressure concentrated crude product that obtains are solid.Residue filters through 2 inches silica gel liners (50% ethyl acetate/hexane class), under reduced pressure concentrates, and obtains 4-chloro-7-(2-trifluoromethyl-phenyl)-quinazoline, is the sallow brown solid.
5. (4-trifluoromethyl-phenyl)-[7-(2-trifluoromethyl-phenyl)-quinazoline-4-yl]-amine
Figure A0380245201432
4-chloro-7-(2-trifluoromethyl-phenyl)-quinazoline (258 milligrams, 0.836 mM) and 4-(trifluoromethyl)-aniline (269 milligrams, 1.67 mMs) refluxed 8 hours in aqueous isopropanol.Cooling solution, collecting precipitation with absolute ether washing (3 times), obtains pure matter (4-trifluoromethyl-phenyl)-[7-(2-trifluoromethyl-phenyl)-quinazoline-4-yl]-amine after filtration, is list-hydrochlorate.Mass spectrum 433.1.
B. (the 4-tert-butyl group-phenyl)-[7-(2-trifluoromethyl-phenyl)-quinazoline-4-yl]-amine (chemical compound 2)
(1.7-2-trifluoromethyl-phenyl)-quinoline-4-phenol
Figure A0380245201433
Combination 7-chloroquinoline-4-phenol (1000 milligrams, 5.55 Bo moles), 2-(trifluoromethyl) phenyl dihydroxy boric acid (1583 milligrams, 8.33 mMs) and toluene (50 milliliters), nitrogen are ventilated in the solution 10 minutes.Adding acid chloride (25 milligrams, 0.11 mM), 2-(dicyclohexyl phosphino-) biphenyl (78 milligrams, 0.22 mM) and potassium phosphate (2353 milligrams, 11.1 mMs) reaches 90 ℃ of heating 16 hours.Allow its cooling, add water (25 milliliters) and ethyl acetate (50 milliliters), remove any insoluble substance by filtering.The separating ethyl acetate layer, water layer is with ethyl acetate (each 25 milliliters) extracting twice.Combination acetic acid ethyl ester extract, dehydration (sodium sulfate) and evaporation.By silica gel column chromatography art purification (94% dichloromethane/5% methanol/1% ammonium hydroxide), obtain 110 milligrams of 7-(2-trifluoromethyl-phenyl)-quinoline-4-phenol, solid is white in color.
2. 4-chloro-7-(2-trifluoromethyl-phenyl)-quinoline
7-(2-trifluoromethyl-phenyl)-quinoline-4-phenol (50 milligrams, 0.17 mM) heated 16 hours down at 90 ℃ in the mixture of phosphoryl chloride phosphorus oxychloride (10 milliliters).The evaporative removal phosphoryl chloride phosphorus oxychloride, (100 gram) on the rocks then careful saturated sodium bicarbonate that adds.With ethyl acetate extraction, dehydration (sodium sulfate) and evaporation obtain 4-chloro-7-(2-trifluoromethyl-phenyl)-quinoline, are the yellowish-brown solid.
3. (the 4-tert-butyl group-phenyl)-[7-(2-trifluoromethyl-phenyl)-quinolyl-4]-amine
Figure A0380245201442
4-chloro-7-(2-trifluoromethyl-phenyl)-quinoline (42 milligrams, 0.14 mM) and 4-(tert-butyl group) aniline (41 milligrams, 0.29 mM) were the mixture reflux of 2-propanol (10 milliliters) 3 hours.Evaporating mixture adds 1M sodium hydroxide (10 milliliters), uses ethyl acetate (each 10 milliliters) extracting twice, and dehydration (sodium sulfate) and evaporation obtain crude product.By silica gel column chromatography art purification, use 75% hexane-eluent ethyl acetate to obtain (the 4-tert-butyl group-phenyl)-[7-(2-trifluoromethyl-phenyl)-quinolyl-4]-amine, solid is white in color.Mass spectrum 420.2.
C. (the 4-tert-butyl group-phenyl)-[7-(2-trifluoromethyl-phenyl)-pyrido [3,2-d] pyrimidine-4-yl]-amine (chemical compound 3)
1. 5-bromo-3-nitropyridine-2-formonitrile HCN
Figure A0380245201451
2,5-two bromo-3-nitropyridines (1.77 grams, 6.3 mMs; Malinowski (1988) Bull.Soc.Chim.Belg.97:51; Also with reference to US 5,801,183) and Cupricin. (0.60 gram, 6.69 mMs) at the solution of N,N-dimethylacetamide (25 milliliters) 100 ℃ of heating 72 hours.After the cooling, mixture is with water (25 milliliters) dilution, with ethyl acetate (each 25 milliliters) extracting twice, then with water (each 25 milliliters) washed twice.The combination acetic acid ethyl ester extract is through dehydration (sodium sulfate), evaporation, and, obtain 5-bromo-3-nitropyridine-2-formonitrile HCN, the gray solid by tomography purification (50% ethyl acetate-hexane) rapidly.
2. 3-amino-5-bromopyridine-2-formonitrile HCN
5-bromo-3-nitropyridine-2-formonitrile HCN (1.5 grams, 5.3 mMs) and stannic chloride dihydrate (5.00 grams, 26.3 mMs) mix in concentrated hydrochloric acid, and it is overnight to be allowed to condition at stirring at room.Handle by postorder on the rocks, carefully add the 10M sodium hydroxide to becoming alkalescence.With ether (200 milliliters) extraction, dehydration (sodium sulfate) and evaporation.Obtain 3-amino-5-bromopyridine-2-formonitrile HCN, gray solid by silica gel column chromatography art (75% hexane-ethyl acetate) purification.
3. 7-bromopyridine [3,2-d] pyrimidine-4-phenol also
3-amino-5-bromopyridine-2-formonitrile HCN (504 milligrams, 2.00 mMs) and sodium acetate (312 milligrams, 3.81 mMs) refluxed 16 hours at the mixture of formic acid (20 milliliters).Handle by being evaporated to the white solid postorder, add 3N sodium hydroxide (50 milliliters).Filter and remove any undissolved material, generate free state pyrimidine phenol by adding concentrated hydrochloric acid once again to reaching pH3 then.Also [3,2-d] pyrimidine-4-phenol is overnight by its drying to collect the 7-bromopyridine.
4. bromo-4-chloropyridine [3,2-d] pyrimidine also
The 7-bromopyridine also the mixture of [3,2-d] pyrimidine-4-phenol (35 milligrams, 0.15 mM) and phosphoryl chloride phosphorus oxychloride (10 milliliters) 90 ℃ of heating 16 hours down.The evaporative removal phosphoryl chloride phosphorus oxychloride, (100 gram) on the rocks then careful saturated sodium bicarbonate that adds.With ethyl acetate extraction twice, dehydration (sodium sulfate) and evaporation obtain also [3,2-d] pyrimidine of bromo-4-chloropyridine, and solid is white in color.
5. (7-bromo-pyrido [3,2-d] pyrimidine-4-the yl)-4-tert-butyl group-phenyl)-amine
Bromo-4-chloropyridine also [3,2-d] pyrimidine (35 milligrams, 0.14 mM) and 4-(tert-butyl group) amine (43 milligrams, 0.29 mM) the mixture reflux of 2-propanol (10 milliliters) 3 hours.Evaporating mixture adds 1M sodium hydroxide (10 milliliters), with ethyl acetate (each 10 milliliters) extracting twice, and dehydration (sodium sulfate), and evaporation obtains crude product.By silica gel column chromatography art purification,, obtain (7-bromo-pyrido [3,2-d] pyrimidine-4-the yl)-4-tert-butyl group-phenyl with 75% hexane-eluent ethyl acetate)-amine, solid is white in color.
6. (the 4-tert-butyl group-phenyl)-[7-(2-trifluoromethyl-phenyl)-pyrido [3,2-d] pyrimidine-4-yl]-amine
Figure A0380245201471
(7-bromo-pyrido [3,2-d] pyrimidine-4-the yl)-4-tert-butyl group-phenyl)-amine (36 milligrams, 0.1 mM), (29 milligrams of 2-(trifluoromethyl) phenyl-dihydroxy boric acid, 0.15 mM) 1, combination in the 2-dimethoxy-ethane (10 milliliters), nitrogen fed mixture 10 minutes.Add tetrakis triphenylphosphine palladium (O) (12 milligrams, 0.01 mM) and 2M sodium carbonate (1 milliliter), heated 48 hours down at 80 ℃.Allow mixture be cooled to room temperature, with water (10 milliliters) dilution, with ethyl acetate (each 10 milliliters) extraction.Dehydration (sodium sulfate), evaporation is used 75% hexane-eluent ethyl acetate purification at preparation property silica gel plate (2000 microns), obtains (the 4-tert-butyl group-phenyl)-[7-(2-trifluoromethyl-phenyl)-pyrido [3,2-d] pyrimidine-4-yl]-amine, is faint yellow solid.Mass spectrum 422.2.
D. (the 4-tert-butyl group-phenyl)-[6-(2-trifluoromethyl-phenyl)-phthalazines-1-yl]-amine (chemical compound 4)
1. 4-bromo-2-two bromomethyls-benzonitrile
Figure A0380245201472
4-bromo-2-methyl-benzonitrile (19.6 grams, 0.1 mole) and bromine (39.0 grams, 0.22 mole) used 500 watts of cold quartz mercury vapor lamp 16 hours in the mixture of carbon tetrachloride (500 milliliters).Allow it be cooled to room temperature and filtration removal succimide.Evaporate obtains 4-bromo-2-two bromomethyls-benzonitrile fully, is yellow powder.
2. 5-bromo-3-hydroxyl-2,3-dihydro-iso-indoles-1-ketone
Figure A0380245201473
4-bromo-2-two bromomethyls-benzonitrile (7.0 grams, 19.8 mMs) and acetonitrile (150 milliliters) combination.Dropwise add the mixture of silver nitrate (7.0 grams, 41.2 mMs) at water (40 milliliters), the translucent yellow liquid of gained refluxed 72 hours.The evaporative removal mixture adds 1M sodium hydroxide (100 milliliters).With ethyl acetate (each 100 milliliters) extracting twice.Solution is through dehydration (sodium sulfate), and evaporation reaches by silica gel column chromatography art (80% hexane-ethyl acetate) purification, obtains 600 milligrams of 4-bromo-2-formoxyl-benzonitriles and 1250 milligrams of 5-bromo-3-hydroxyls-2,3-dihydro-iso-indoles-1-ketone, and solid is white in color.
3. 6-bromo-phthalazines-1-phenol
Figure A0380245201481
5-bromo-3-hydroxyl-2,3-dihydro-iso-indoles-1-ketone (1.0 grams, 4.39 mMs) and hydrazine hydrate (10 milliliters) combination allow suspension at room temperature stir 16 hours.Collect 6-bromo-phthalazines-1-phenol, solid is white in color.
4. 6-bromo-1-chloro-phthalazines
Figure A0380245201482
6-bromo-phthalazines-1-phenol (300 milligrams, 1.33 mMs) heated 2 hours at 90 ℃ at the mixture of phosphoryl chloride phosphorus oxychloride (10 milliliters).The evaporative removal phosphoryl chloride phosphorus oxychloride, (100 gram) on the rocks, the then careful saturated sodium bicarbonate that adds.With ethyl acetate extraction, dehydration (sodium sulfate) and evaporation obtain 4-chloro-7-(2-trifluoromethyl-phenyl)-quinoline, and solid is white in color.
5. (6-bromo-phthalazines-1-yl)-(the 4-tert-butyl group-phenyl)-amine
6-bromo-1-chloro-phthalazines (500 milligrams, 2.05 mMs) and 4-(tert-butyl group) aniline (611 milligrams, 4.10 mMs) were the mixture reflux of 2-propanol (10 milliliters) 3 hours.The evaporative removal mixture adds 1M sodium hydroxide (10 milliliters), and with ethyl acetate (each 10 milliliters) extracting twice, dehydration (sodium sulfate) and evaporation obtain crude product.By silica gel column chromatography art purification, with the dichloromethane eluting,, obtain (6-bromo-phthalazines-1-yl)-(the 4-tert-butyl group-phenyl)-amine then with 95% methylene chloride-methanol eluting, solid is white in color.
6. (the 4-tert-butyl group-phenyl)-[6-(2-trifluoromethyl-phenyl)-phthalazines-1-yl]-amine
(60 milligrams of (6-bromo-phthalazines-1-yl)-(the 4-tert-butyl group-phenyl)-amine, 0.19 mM), 2-(trifluoromethyl) phenyl-dihydroxy boric acid (50 milligrams, 0.26 mM) is 1,2-dimethoxy-ethane (10 milliliters) combination, nitrogen are ventilated into mixture 10 minutes.Add tetrakis triphenylphosphine palladium (O) (12 milligrams, 0.01 mM) and 2M sodium carbonate (1 milliliter), 80 ℃ of heating 48 hours.Allow mixture be cooled to room temperature, with 10 milliliters of dilutions of water, with ethyl acetate (each 10 milliliters) extracting twice.Dehydration (sodium sulfate), evaporation reaches at preparation property silica gel plate (2000 microns) and uses 75% hexane-eluent ethyl acetate purification, obtains (the 4-tert-butyl group-phenyl)-[6-(2-trifluoromethyl-phenyl)-phthalazines-1-yl]-amine, is the deadgress solid.Mass spectrum 421.2.
F. (the 4-tert-butyl group-phenyl)-[7-(2-trifluoromethyl-phenyl)-pyrido [2,3-d] pyrimidine-4-yl]-amine (chemical compound 5 and 6)
1. ketone group-3-hydrocinnamicaldehyde
The mixture heated to 50 of toluene and ethoxyquin sodium (40 milliliter of 21% alcoholic solution) ℃.Add 2-trifluoromethyl acetophenone (20.0 grams, 0.11 mole) and Ethyl formate (11.8 grams, 0.16 mole), be allowed to condition at 65 ℃ and stirred 12 hours.Mixture is cooled to room temperature, adds 300 milliliters of ether.Collecting precipitation obtains the sodium salt of 3-ketone group-3-hydrocinnamicaldehyde.
2. 7-(2-trifluoromethyl-phenyl)-1H-pyrido [2,3-d] pyrimidine-2, the 4-diketone
Figure A0380245201501
The sodium salt of fine segmentation 3-ketone group-3-hydrocinnamicaldehyde (10.0 grams, 0.043 mole) adds 50 milliliter of 90% phosphoric acid.Be stirred to dissolving fully.Dissolve 6-amino-1H-pyrimidine-2 in addition in a similar manner, 4-diketone (5.7 grams, 0.043 mole) is at 50 milliliter of 90% phosphoric acid.With two kinds of solution combinations, be allowed to condition at 100 ℃ and stirred 12 hours.Allow solution be cooled to room temperature, add 300 ml waters, the collection product is is stained with viscous solid.Use ether grinds, and obtains 7-(2-trifluoromethyl-phenyl)-1H-pyrido [2,3-d] pyrimidine-2, the 4-diketone, and solid is white in color.
3. 2,4-two chloro-7-(2-trifluoromethyl-phenyl)-pyrido [2,3-d] pyrimidine
Figure A0380245201502
7-(2-trifluoromethyl-phenyl)-1H-pyrido [2,3-d] pyrimidine-2, the mixture of 4-diketone (5.0 grams, 0.016 mole) and phosphoryl chloride phosphorus oxychloride (100 milliliters) was 90 ℃ of heating 36 hours.The evaporative removal phosphoryl chloride phosphorus oxychloride, (400 gram) on the rocks, the then careful saturated sodium bicarbonate that adds.With ethyl acetate extraction twice, dehydration (sodium sulfate) and evaporation obtain 2,4-two chloro-7-(2-trifluoromethyl-phenyl)-pyrido [2,3-d] pyrimidine.
4. (the 4-tert-butyl group-phenyl)-[2-chloro-7-(2-trifluoromethyl-phenyl)-pyrido [2,3-d] pyrimidine-4-yl]-amine (chemical compound 5)
Figure A0380245201511
(260 milligrams of diisopropyl ethyl amines, 2.0 mM) in the mixture of acetonitrile (5 milli), add (124 milligrams of tert-butyl group aniline, 1.0 mM), then add (the 4-tert-butyl group-phenyl)-[2-chloro-7-(2-trifluoromethyl-phenyl)-pyrido [2,3-d] pyrimidine-4-yl]-amine (310 milligrams, 1.0 mMs).Mixture heated to 80 ℃ 6 hours.The evaporative removal solvent divides to be dissolved in 1M sodium hydroxide and ethyl acetate.Solvent is through dehydration (sodium sulfate) and evaporation.Obtain an aniline (the 4-tert-butyl group-phenyl)-[2-chloro-7-(2-trifluoromethyl-phenyl)-pyrido [2,3-d] pyrimidine-4-yl]-amine by silica gel column chromatography art (1: 1 hexane/ethyl acetate) purification, be yellow solid.
5. (the 4-tert-butyl group-phenyl)-[7-(2-trifluoromethyl-phenyl)-pyrido [2,3-d] pyrimidine-4-yl]-amine (chemical compound 6)
(the 4-tert-butyl group-phenyl)-[2-chloro-7-(2-trifluoromethyl-phenyl)-pyrido [2,3-d] pyrimidine-4-yl]-the 2-chlorine substituent of amine can use the known multiple reducing condition of organic synthesis people in the industry to remove, for example use hydrogenolysis or remove (for example with reference to Hudlicky with aluminum hydride reducing agent, M. organic chemistry reduction, the single chapter 188:1996 of ACS).
F.[7-(3-fluoro-pyridine-2-yl)-quinazoline-4-yl]-(5-trifluoromethyl-pyridine-2-yl)-amine (chemical compound 7)
1. 7-bromo-4-chloro-quinazoline
7-bromo-3H-quinazoline-4-one (1.24 grams, 0.0055 mole) refluxed 3.5 hours at the solution of phosphoryl chloride phosphorus oxychloride.Under reduced pressure remove excessive phosphorus chloride, the residue branch is dissolved in ethyl acetate and saturated aqueous sodium bicarbonate.Ethyl acetate layer is under reduced pressure removed solvent through dehydration, obtains 7-bromo-4-chloro-quinazoline, is yellow solid.
2. (7-bromo-quinazoline-4-yl)-(5-trifluoromethyl-pyridine-2-yl)-amine
Figure A0380245201522
The mixture of 7-bromo-4-chloro-quinazoline (200 milligrams, 0.821 mM) and 2-amino-5-trifluoromethyl-pyridine (239 milligrams, 1.48 mMs) was 230 ℃ of heating 2 minutes.Solid residue cooling and branch are dissolved in ethyl acetate and 10% sodium hydroxide.Ethyl acetate layer is under reduced pressure removed solvent through dehydration (sodium sulfate), through tomography purification rapidly, obtains (7-bromo-quinazoline-4-yl)-(5-trifluoromethyl-pyridine-2-yl)-amine, is yellow solid.
3. 3-fluoro-2-tributyl tin alkyl-pyridine
Figure A0380245201523
2-bromo-3-fluoro-pyridine (542 milligrams, 3.08 mMs) uses the dry ice-propanone bath to be cooled to-78 ℃ at the solution of anhydrous THF.Dropwise add n-BuLi (1.6M at THF, 2.0 milliliters) to reactant mixture through syringe with 20 fens clock times.After 1.5 hours, slowly add tributyltin chloride-78 ℃ of stirrings, remove cooling bath through syringe.After 2 hours, the reactant mixture branch is dissolved in ethyl acetate and saline solution, and ethyl acetate layer is through dehydration (sodium sulfate) and under reduced pressure remove solvent.Tomography (ether/hexane) obtains 3-fluoro-2-tributyl tin alkyl-pyridine rapidly, is water white oil.
(4.[7-3-fluoro-pyridine-2-yl)-quinazoline 4-yl]-(5-trifluoromethyl-pyridine-2-yl)-amine
Figure A0380245201531
Use the program of similar preamble explanation, prepare [7-(3-fluoro-pyridine-2-yl)-quinazoline-4-yl]-(5-trifluoromethyl-pyridine-2-yl)-amine to 3-fluoro-2-tributyl tin alkyl-pyridine via coupling (7-bromo-quinazoline-4-yl)-(5-trifluoromethyl-pyridine-2-yl)-amine.Mass spectrum 385.1.
G. (the 4-tert-butyl group-phenyl)-(7-pyridine-2-base-quinazoline-4-yl)-amine (chemical compound 8)
1. 4-bromo-2-nitrobenzonitrile
1,4-two bromo-2-nitro-benzene (3.56 mM) and Cupricin. (3.74 mM) stirred 5 hours at 100 ℃ at the mixture of DMA (4 milliliters).Be cooled to room temperature, with the ethyl acetate dilution, filter through the C ore deposit, organic layer washs with saline solution, with sodium sulfate dehydration and vacuum concentration.Residue obtains 4-bromo-2-nitrobenzonitrile by tomography (4: 1 hexane/ethyl acetate) purification rapidly.
2. 2-amino-4-bromo-benzonitrile
4-bromo-2-nitrobenzonitrile (2.60 grams, 0.0115 mole) is divided into several parts at 0 ℃ and adds SnCl in the suspension of 12N hydrochloric acid 2-2H 2O.Generate white precipitate during the reaction high degree of agitation.On the rocks after 1 hour to reaction vessel, then add 10N sodium hydroxide to solution and be alkalescence.Aqueous mixture is with ether extraction (2 times) and with ethyl acetate extraction (1 time), and the combination organic layer washs with saline solution.Solution is through dehydration (sodium sulfate) and under reduced pressure remove solvent, obtains 2-amino-4-bromo-benzonitrile, is the light brown solid.
3. 7-bromo-3H-quinazoline-4-one
In the solution of formic acid, once add sodium acetate (435 milligrams, 5.30 mMs) at 2-amino-4-bromo-benzonitrile (550 milligrams, 2.79 mMs).Reaction mixture refluxed 16 hours is under reduced pressure removed formic acid then and is obtained solid.Add 20% aqueous sodium hydroxide and stirred 1 hour, remove not dissolved solid after filtration, filtrate is made white solid with the 12N hcl acidifying.Solid is collected after filtration, with water washing (5 times) and with ether washing (1 time), obtains 7-bromo-3H-quinazoline-4-one, is pale solid.
4. 7-pyridine-2-base-3H-quinazoline-4-one
(100 milligrams of 7-bromo-3H-quinazoline-4-ones, 0.444 mM) in the mixture of toluene/dioxy hexane (3: 1), add 2-tributyl tin alkyl pyridine (162 milligrams, 0.444 mM), then add four-(triphenylphosphine) palladiums (O) (26 milligrams, 0.022 mM).Nitrogen is by solution 10 minutes, then the solution to 115 in the heated and stirred ℃ under nitrogen atmosphere.After several minutes, reactant mixture becomes homogenizing.After 16 hours, reactor vessel cooled, precipitation is collected after filtration.Solid washs with 25% ethyl acetate/hexane, then with hexane wash, obtains 7-pyridine-2-base-3H-quinazoline-4-one, is the light brown solid.
5. (the 4-tert-butyl group-phenyl)-(7-pyridine-2-base-quinazoline-4-yl)-amine
Figure A0380245201551
Use similar aforementioned program, by 4-chloro-7-pyridine-2-base-quinazoline and 4-tert-butylamine preparation (the 4-tert-butyl group-phenyl)-(7-pyridine-2-base-quinazoline-4-yl)-amine.Mass spectrum 354.2.
H. (the 4-tert-butyl group-phenyl)-[7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-amine hydrochlorate (chemical compound 9)
1. 2-(4-bromo-phenyl)-3-(trifluoromethyl)-pyridine
At 2-bromo-3-(trifluoromethyl)-pyridine (2.26 mM), 4-bromo-phenyl dihydroxy boric acid (2.49 mM) reaches in the process mixture of degasification of the 2M sodium carbonate (5.65 mM) of DME (10 milliliters), adds Pd (PPh under nitrogen atmosphere 3) 4(0.09 mM).Mixture concentrates 80 ℃ of stirred overnight, uses ethyl acetate extraction.With sodium sulfate dehydration, vacuum concentration,, obtain 2-(4-bromo-phenyl)-3-(trifluoromethyl)-pyridine by tomography (4: 1 hexane/ethyl acetate) purification rapidly.
2. 2-(4-bromo-3-nitro-phenyl)-3-(trifluoromethyl)-pyridine
At 2-(4-bromo-phenyl)-3-(trifluoromethyl)-pyridine (0.93 mM) careful fuming nitric aicd (2 milliliters) that adds in the solution of sulphuric acid (4 milliliters).Mixture at room temperature stirred 30 minutes.Mixture is to frozen water (20 milliliters), collecting precipitation.Be deposited in the ethyl acetate and dissolve, use the saturated sodium bicarbonate neutralization, with the sodium sulfate dehydration, vacuum concentration obtains 2-(4-bromo-3-nitro-phenyl)-3-(trifluoromethyl)-pyridine.
3. 2-nitro-4-(3-trifluoromethyl-pyridine-2-yl)-benzonitrile
Figure A0380245201561
Add CuCN (0.60 mM) to 2-(4-bromo-3-nitro-phenyl)-3-(trifluoromethyl)-pyridine (0.55 mM) at the solution of DMA (4 milliliters).Mixture stirred 4 hours down at 110 ℃.Be cooled to room temperature,, filter through C ore deposit liner with 20 milliliters of ethyl acetate dilutions.Filtrate is washed with saline solution, and with sodium sulfate dehydration, vacuum concentration and by tomography (1: 1 hexane/ethyl acetate) purification rapidly obtains 2-nitro-4-(3-trifluoromethyl-pyridine-2-yl)-benzonitrile.
4. 2-amino-4-(3-trifluoromethyl-pyridine-2-yl)-benzonitrile
To 2-nitro-4-(3-trifluoromethyl-pyridine-2-yl)-benzonitrile (0.44 mM) concentrated hydrochloric acid (6 milliliters) with the frozen water cooling solution in add SnCl 2(1.457 mM).Mixture at room temperature stirred 2 hours.The neutralization of use sodium hydroxide, with ethyl acetate extraction, with the sodium sulfate dehydration, and vacuum concentration.Residue obtains 2-amino-4-(3-trifluoromethyl-pyridine-2-yl)-benzonitrile by tomography (4: 1 hexane/ethyl acetate) purification rapidly.
5. 7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-phenol
2-amino-4-(3-trifluoromethyl-pyridine-2-yl)-benzonitrile (0.41 mM) refluxed 16 hours in formic acid (10 milliliters) with sodium acetate (1.23 mM).Solvent is removed in vacuum evaporation, and residue is suspended in 20 milliliter of 20% sodium hydroxide, at room temperature stirs 30 minutes.Filter,,, obtain 7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-phenol with sodium sulfate dehydration and vacuum concentration with ethyl acetate extraction.
6. 4-chloro-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline
7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-phenol (0.38 mM) is at POCl 3(5 milliliters) refluxed 18 hours.Solvent is removed in vacuum evaporation, then with the careful neutralization of sodium bicarbonate and with ethyl acetate extraction.With the sodium sulfate dehydration, vacuum concentration obtains 4-chloro-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline.
7. (the 4-tert-butyl group-phenyl)-[7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-amine hydrochlorate
Figure A0380245201572
4-chloro-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline (0.16 mM) and the 4-tert-butyl group-aniline (0.32 mM) stirred 6 hours at 80 ℃ at IPA (4 milliliters).Cooling mixture, collecting precipitation obtains (the 4-tert-butyl group-phenyl)-[7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-amine hydrochlorate.Mass spectrum 422.2.
I. (the 4-tert-butyl group-phenyl)-[2-methyl-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-amine Hydrochlorate (chemical compound 10)
1. 2-amino-4-(3-trifluoromethyl-pyridine-2-yl)-benzyl amide
2-amino-4-(3-trifluoromethyl-pyridine-2-yl)-benzonitrile (0.50 mM) stirred 1 hour down at 110 ℃ at the mixture of 70% sulphuric acid (10 milliliters).Be cooled to room temperature, with the sodium bicarbonate neutralization, with ethyl acetate extraction, with sodium sulfate dehydration and vacuum concentration.Residue obtains 2-amino-4-(3-trifluoromethyl-pyridine-2-yl)-benzyl amide by tomography (3: 2 hexane class/ethyl acetate) purification rapidly.
2. 2-acetylaminohydroxyphenylarsonic acid 4-(3-trifluoromethyl-pyridine-2-yl)-benzyl amide
In the solution of THF (5 milliliters), add chloroacetic chloride (0.55 mM) to 2-amino-4-(3-trifluoromethyl-pyridine-2-yl)-benzyl amide (0.5 mM) and pyridine (0.55 mM).Mixture was stirring at room 10 minutes.Through vacuum concentration, with ethyl acetate extraction, with the saline solution washing, with sodium sulfate dehydration and vacuum concentration.Use ether to grind and obtain 2-acetylaminohydroxyphenylarsonic acid 4-(3-trifluoromethyl-pyridine-2-yl)-benzyl amide.
3. 2-methyl-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-phenol
Figure A0380245201583
2-acetylaminohydroxyphenylarsonic acid 4-(3-trifluoromethyl-pyridine-2-yl)-benzyl amide is suspended in 20 milliliter of 20% sodium hydroxide, stirring at room 30 minutes.Filter, be acidified to pH=6, with ethyl acetate extraction, vacuum concentration obtains 2-methyl-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-phenol.
4. 4-chloro-2-methyl-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline
Use similar aforementioned program, prepare 4-chloro-2-methyl-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline by 2-methyl-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-phenol.
5. (the 4-tert-butyl group-phenyl)-[2-methyl-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-amine
Use similar aforementioned program, via condensation 4-chloro-2-methyl-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline and 4-tert-butyl group aniline, preparation (the 4-tert-butyl group-phenyl)-[2-methyl-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-amine.Mass spectrum 436.2.
J.[7-(3-methyl-pyridine-2-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine (chemical compound 11)
1. 7[B (OH) 2]-3H-quinazoline-4-one
3-amino-4-ethoxycarbonyl-phenyl dihydroxy boric acid (1.46 grams, 0.007 mole) according to people such as Torssell (1957) Arkiv Kemi10:497 preparation refluxed 7 hours at the mixture of methyl cellosolve with carbonamidine acetas (1.17 grams, 0.008 mole).Add extra equivalent carbonamidine acetas and continue and refluxed 16 hours.The cooling dark solution is under reduced pressure removed solvent.Add about 100 ml waters, stirred 10 minutes, collect light gray solid at sintered glass funnel.Solid is with water washing (3 times), and dehydration obtains 7[B (OH) by the methanol recrystallize 2]-3H-quinazoline-4-one, solid is white in color.
2. 7-(3-methyl-pyridine-2-yl)-3H-quinazoline-4-one
Figure A0380245201601
7[B (OH) 2]-3H-quinazoline-4-one (115 milligrams, 0.605 mM), 2-bromo-3-methyl-pyridine (103 milligrams, 0.605 mM), the solution of sodium carbonate (0.757 milliliter, 1.51 mMs, 2M aqueous solution) and DMF (4 milliliters) removed 10 minutes with nitrogen sweep.Four-(triphenylphosphine) palladiums (O) (35 milligrams, 0.03 mM) that add catalytic amount were 95 ℃ of heating 16 hours.Reaction mixture is with the water dilution and with ethyl acetate extraction.The combination organic layer under reduced pressure concentrates through dehydration (sodium sulfate), and crude product uses silica gel column chromatography art (ethanol/methylene) purification to obtain 7-(3-methyl-pyridine-2-yl)-3H-quinazoline-4-one.
(3.[7-3-methyl-pyridine-2-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine
Use similar aforementioned program (for example reference reaction Fig. 1 and 2), be divided into two steps preparation [7-(3-methyl-pyridine-2-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine by 7-(3-methyl-pyridine-2-yl)-3H-quinazoline-4-one.Mass spectrum 380.1.
K. (the 4-tert-butyl group-phenyl)-[7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-amine hydrochlorate (chemical compound 9)
1. 2-p-methylphenyl-3-trifluoromethyl-pyridine
At 2-chloro-3-(trifluoromethyl)-pyridine (70.1 mM), p-methylphenyl dihydroxy boric acid (70.6 mM) and 2M sodium carbonate (175.0 mM) add Pd (PPh DME's (200 milliliters) through in the mixture of degasification under nitrogen 3) 4(2.8 mM).Mixture concentrates, with ethyl acetate extraction 80 ℃ of stirred overnight.With the sodium sulfate dehydration, vacuum concentration by the silica gel liner, obtains 2-p-methylphenyl-3-trifluoromethyl-pyridine.
2. 2-(4-methyl-3-nitro-phenyl)-3-(trifluoromethyl)-pyridine
At 2-p-methylphenyl-3-trifluoromethyl-pyridine (8.4 mM) careful fuming nitric aicd (2 milliliters) that adds in the solution of sulphuric acid (6 milliliters).Mixture was stirring at room 60 minutes.Mixture is poured frozen water (30 milliliters) into, with ethyl acetate extraction, with the neutralization of 1N sodium hydroxide, with sodium sulfate dehydration and vacuum concentration, obtains 2-(4-methyl-3-nitro-phenyl)-3-(trifluoromethyl)-pyridine.
3. 2-nitro-4-(3-trifluoromethyl-pyridine-2-yl)-benzoic acid
In the solution of the mixture of pyridine (10 milliliters) and water (5 milliliters), be divided into several parts at 2-(4-methyl-3-nitro-phenyl)-3-(trifluoromethyl)-pyridine (7.1 mM) and add KMnO 4(25.3 mM).Mixture stirs at 110 ℃ and added 25.3 mM KMnO in 4 hours then again 4And 10 ml waters.Mixture is 110 ℃ of stirred overnight.Be cooled to room temperature, filter through C ore deposit liner.Filtrate is through vacuum concentration, with the water dilution, with the ethyl acetate wash water solution.To obtain 2-nitro-4-(3-trifluoromethyl-pyridine-2-yl)-benzoic acid with aqueous solution and collecting precipitation in the 2N sulphuric acid.
4. 2-amino-4-(3-trifluoromethyl-pyridine-2-yl)-benzoic acid
Figure A0380245201621
2-nitro-4-(3-trifluoromethyl-pyridine-2-yl)-benzoic acid (3.84 mM) uses 10%-Pd-C (150 milligrams) hydrogenation and overnight in the solution of 95% ethanol (100 milliliters).Filter through C ore deposit liner, concentrating filter liquor obtains 2-amino-4-(3-trifluoromethyl-pyridine-2-yl)-benzoic acid.
5. 7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-phenol
2-amino-4-(3-trifluoromethyl-pyridine-2-yl)-benzoic acid (1.95 mM) stirred 4 hours at 145 ℃ at the mixture of Methanamide (10 milliliters).Be cooled to room temperature, obtain 7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-phenol with dilution of 20 ml waters and collecting precipitation.
6. (the 4-tert-butyl group-phenyl)-[7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-amine hydrochlorate
Figure A0380245201623
Use similar program (for example reference reaction Fig. 1 and 2), be divided into two steps preparation (the 4-tert-butyl group-phenyl)-[7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-amine hydrochlorate by 7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-phenol.Mass spectrum 422.2.
L.[6-(propane-2-sulfonyl)-pyridin-3-yl]-[7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline -4-yl]-amine hydrochlorate (chemical compound 12)
1. 2-isopropyl sulfane base-5-nitro-pyridine
Figure A0380245201631
2-sulfydryl-5-nitropyridine (10.0 mM) and sodium hydride (14.0 mM) at the mixture of DMA (10 milliliters) stirring at room 30 minutes.Add 2-iodopropane (11.0 mM) and overnight in stirring at room.With the water dilution, with ethyl acetate extraction, with the saline solution washing, with sodium sulfate dehydration and vacuum concentration.Residue obtains 2-isopropyl sulfane base-5-nitro-pyridine by tomography (9: 1 hexane/ethyl acetate) purification rapidly.
2. 5-nitro-2-(propane-2-sulfonyl)-pyridine
2-isopropyl sulfane base-5-nitro-pyridine (3.5 mM) and KMnO 4(14.1 mM) is overnight 110 ℃ of heating at the mixture of acetic acid (15 milliliters).Filter, concentrating filter liquor reaches and neutralizes with sodium bicarbonate.Use ethyl acetate extraction,,, obtain 2-(propane-2-sulfonyl)-5-nitro-pyridine with sodium sulfate dehydration and vacuum concentration with the saline solution washing.
3. 6-(propane-2-sulfonyl)-pyridin-3-yl amine
2-(propane-2-sulfonyl)-5-nitro-pyridine (0.44 mM) is suspended in 10 milliliters of concentrated hydrochloric acid, adds stannic chloride dihydrate (1.43 mM) and stirring at room 2 hours.The neutralization of use sodium bicarbonate.With ethyl acetate extraction,, obtain 6-(propane-2-sulfonyl)-pyridin-3-yl amine with sodium sulfate dehydration and vacuum concentration with the saline solution washing.
(4.[6-propane-2-sulfonyl)-pyridin-3-yl]-[7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-amine hydrochlorate
Figure A0380245201641
[6-(propane-2-sulfonyl)-pyridin-3-yl]-[7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-amine hydrochlorate that uses the described method of embodiment 1H.7 to obtain.Mass spectrum 473.1.
M. quinazoline-4-ylamine analogues of being substituted of other representativeness
Use conventional the modification, the change starting material also adopts additional step to prepare other chemical compound that the present invention is contained.The chemical compound that Table II is enumerated is to use the preceding method preparation to have the modification of obviously easily seeing.
Table II
The quinazoline that representativeness is substituted-4-ylamine analogues
Figure A0380245201661
Figure A0380245201681
Figure A0380245201691
Figure A0380245201701
Figure A0380245201721
Figure A0380245201751
Figure A0380245201771
Figure A0380245201791
Figure A0380245201811
Figure A0380245201841
The chemical compound of other preparation is recited in Table III.That uses is abbreviated as: the Ph=phenyl; The Py=pyridine; The Me=methyl; The Et=ethyl; The tBu=tert-butyl; Thia=(1,3,4) thiadiazoles; The pyraz=1H-pyrazoles; The isopr=isopropyl; The MeO=methoxyl group; The EtO=ethyoxyl; The PrO=propoxyl group; The MeA=methylamino; The EtA=ethylamino; PrA=propyl group amino; BuA=butyl amino; The DMA=dimethylamino; The DEA=diethylamino.The variable position of Table III indication is shown in following structural formula:
Table III
Chemical compound Ar 1 Ar 2 R 2 ??MS
143. 2-CF 3-Ph 4-cyclohexyl-Ph H ??447.2
144. 2-CF 3-Ph 4-CF 3-Ph isopr ??475.1
145. 2-CF 3-Ph 4-tBu-Ph CF 3 ??489.2
146. 2-Cl-Ph 4-(CF(CF 3) 2)-Ph H ??499.1
147. 2-F-Ph 4-(CF(CF 3) 2)-Ph H ??483.1
148. 2-MeO-Ph 4-(CF(CF 3) 2)-Ph H ??495.1
149. 2-CF 3-Ph 5-tBu-isox-3yl H ??412.1
150. 2-CF 3-Ph 5-tBu-thia-2yl H ??429.1
151. 2-CF 3-Ph 5-tBu-pyraz-3yl H
152. 3-CF 3-Py-2yl 6-CF 3-Py-3yl -NH-(6-CF 3-Py-3yl) ??595.1
153. 3-CF 3-Py-2yl 6-Me-Py-3yl H ??381.1
154. 3-CF 3-Py-2yl 5-Cl-Py-2yl H
155. Py-2yl 4-CF 3-Ph H ??366.1
156. 3-F-Py-2yl 4-tBu-Ph H ??372.2
157. 3-F-Py-2yl 4-CF 3-Ph H ??384.1
158. 3-Cl-Py-2yl 4-tBu-Ph H ??388.1
159. 3-Cl-Py-2yl 4-CF 3-Ph H ??400.1
160. 3-CF 3-Py-2yl 4-CF 3-Ph H ??434.1
161. 3-CF 3-Py-2yl 4-F-Ph H ??384.1
162. 3-CF 3-Py-2yl 4-Cl-Ph H ??400.1
163. 3-CF 3-Py-2yl 4-acetyl group-Ph H ??408.1
164. 3-CF 3-Py-2yl 4-cyano group-Ph H ??391.1
Chemical compound Ar 1 Ar 2 R 2 ??MS
165. 3-CF 3-Py-2yl 4-(CF(CF 3) 2)-Ph H ??534.1
166. 3-CF 3-Py-2yl 4-CF 3-Ph Me ??448.1
167. 3-CF 3-Py-2yl 4-CF 3-Ph Cl
168. 3-CF 3-Py-2yl 4-CF 3-Ph -O-CH 2CH 2OH ??494.1
169. 3-CF 3-Py-2yl 4-CF 3-Ph -O-CH 2CH 2-DMA ??521.2
170. 3-CF 3-Py-2yl 4-CF 3-Ph -O-(CH 2) 3-DMA ??535.2
171. 3-CF 3-Py-2yl 4-CF 3-Ph MeA ??463.1
172. 3-CF 3-Py-2yl 4-CF 3-Ph DMA ??477.1
173. 3-CF 3-Py-2yl 4-isopr-Ph H ??408.2
174. 3-CF 3-Py-2yl 6-MeO-Py-3yl H ??397.1
175. 3-CF 3-Py-2yl 3-Me-4-isopr-Ph H ??422.2
176. 3-MeO-Py-2yl 4-CF 3-Ph H ??396.1
177. 3-Pro-Py-2yl 4-CF 3-Ph H ??424.2
178. 3-Pro-Py-2yl 4-isopr-Ph H ??398.2
179. 2-Cl-Ph 4-CF 3-Ph H ??399.1
180. 2，4-diCl-Ph 4-CF 3-Ph H ??433.0
181. 2-Cl-Ph 4-tBu-Ph H ??387.2
182. 2，4-diCl-Ph 4-tBu-Ph H ??421.1
183. 3-CF 3-Py-2yl 4-CF 3-Ph MeO
184. 3-Cl-Py-2yl 6-CF 3-Py-3yl H ??401.1
185. 2-CF 3-Ph 4-CF 3-Ph Morpholine-4 base ??519.1
186. 3-CF 3-Py-2yl 3-MeO-Ph H ??396.1
187. 3-CF 3-Py-2yl 6-tBu-Py-3yl H ??423.2
188. 3-Cl-Py-2yl 6-tBu-Py-3yl H ??389.1
189. 3-Pro-Py-2yl 6-tBu-Py-3yl H ??413.2
190. 3-CF 3-Py-2yl 4-(isopr-SO 2)-Ph H ??472.1
191. 3-CF 3-Py-2yl 5-CF 3-Py-2yl Me ??449.1
192. 3-CF 3-Py-2yl 6-tBu-Py-3yl Me ??437.2
193. 3-CF 3-Py-2yl 6-CF 3-Py-3yl CF 3 ??503.1
194. 3-CF 3-Py-2yl 6-CF 3-Py-3yl n-Pr ??477.1
Chemical compound Ar 1 Ar 2 R 2 ??MS
195. 3-CF 3-Py-2yl 6-tBu-Py-3yl n-Pr ??465.2
196. 3-CF 3-Py-2yl 5-CF 3-Py-2yl n-Pr ??477.1
197. 3-CF 3-Py-2yl 6-CF 3-Py-3yl Et ??463.1
198. 3-CF 3-Py-2yl 6-tBu-Py-3yl Et
199. 3-CF 3-Py-2yl 6-tBu-Py-3yl CF 3 ??491.2
200. 3-CF 3-Py-2yl 4-(tBu-NH-SO 2)-Ph Me ??515.2
201. 3-CF 3-Py-2yl 6-isopr-Py-3yl H ??409.2
202. 3-CF 3-Py-2yl 6-isopr-Py-3yl n-Pr ??451.2
203. 3-CF 3-Py-2yl 6-isopr-Py-3yl Me ??423.2
204. 3-CF 3-Py-2yl 6-tBu-Py-3yl -O-(CH 2)CH 2OH ??483.2
205. 3-CF 3-Py-2yl 6-CF 3-Py-3yl Cl ??469.1
206. 3-CF 3-Py-2yl 6-CF 3-Py-3yl -N-(CH 2)CH 2(CH 3) 2 ??520.2
207. 3-CF 3-Py-2yl 4-CF 3-Ph CN ??325.0
208. 3-CF 3-Py-2yl 4-CF 3-Ph Ph ??510.1
209. 3-CF 3-Py-2yl 5-CF 3-Py-2yl Chloromethyl ??483.1
210. 3-CF 3-Py-2yl 4-CF 3-Ph Chloromethyl
211. 3-NO 2-Py-2yl 6-CF 3-Py-3yl H ??412.1
212. 3-CF 3-Py-2yl 4-CF 3-Ph -CH 2SO 2CH 3 ??526.1
213. 3-CF 3-Py-2yl 6-CF 3-Py-3yl -CH 2SO 2CH 3 ??527.1
214. 3-Cl-Py-2yl 6-CF 3-Py-3yl Me ??415.1
215. 3-CF 3-Py-2yl 4-(CH 3SO 2)-Ph H ??445.1
216. 2-(CH 3SO 2)-Ph 4-CF 3-Ph H
217. 2-(CH 3SO 2)-Ph 6-CF 3-Py-3yl H
218. 3-(DMA-SO 2)-Py-2yl 4-CF 3-Ph H
219. 2-(CH 3SO 2)-Ph 4-CF 3-Ph Me
220. 2-(CH 3SO 2)-Ph 6-CF 3-Py-3yl Me
221. 3-(DMA-SO 2)-Py-2yl 4-CF 3-Ph Me
222. 3-CF 3-Py-2yl 4-CF 3-Ph -(CH 2) 2-S-Me
223. 3-CF 3-Py-2yl 6-CF 3-Py-3yl -(CH 2) 2-S-Me
Chemical compound Ar 1 Ar 2 R 2 ??MS
224. 3-CF 3-Py-2yl 4-CF 3-Ph -(CH 2) 2-SO 2-Me
225. 3-cyano group-Py-2yl 4-CF 3-Ph Me
226. 3-Cl-Py-2yl 4-(CF 3SO 2)-Ph H ??464.0
227. 3-CF 3-Py-2yl 4-CF 3-Ph -CH 2-CN ??473.1
228. 3-CH 3-Py-2yl 4-tBu-Ph H ??368.2
229. 3-CH 3-Py-2yl 6-CF 3-Py-3yl H ??381.1
230. 3-CH 3-Py-2yl 4-isopr-Ph H ??354.2
231. 3-CH 3-Py-2yl 4-Et-Ph H ??340.2
The chemical compound of other preparation is recited in Table IV.The abbreviation of using as preamble to as described in the Table III.Variable position is presented at following structural formula:
Figure A0380245201881
Table IV
Chemical compound Ar 1 Ar 2 R 2 MS
232. 2-CF 3-Ph 4-CF 3-Ph -NH-(4-CF 3-Ph) 593.1
233. 2-CF 3-Ph 4-(CF 3-SO 2)-Ph Cl 532.2
234. 2-CF 3-Ph 4-(morpholine-4yl-SO 2)-Ph Cl 549.1
235. 2-CF 3-Ph 4-tBu-Ph -N-CH 2CH(CH 3) 2 493.2
236. 2-CF 3-Ph 4-(morpholine-4yl-SO 2)-Ph -N-CH 2CH(CH 3) 2 586.2
237. 2-CF 3-Ph 4-(morpholine-4yl-SO 2)-Ph -N-isopr 572.2
238. 2-CF 3-Ph 4-(morpholine-4yl-SO 2)-Ph -N-(CH 2) 2CH(CH 3) 2 600.2
239. 2-CF 3-Ph 4-(morpholine-4yl-SO 2)-Ph N-(CH 2) 6CH(CH 3) 2
240. 2-CF 3-Ph 6-CF 3-Py-3yl H 435.1
241. 2-CF 3-Ph 5-CF 3-Py-2yl Cl 469.1
242. 3-Cl-Py-2yl 4-tBu-Ph H 389.1
Chemical compound Ar 1 Ar 2 R 2 ??MS
243. 3-Cl-Py-2yl 4-CF 3-Ph H ??401.1
244. 3-Cl-Py-2yl 4-[C(CH 3) 2CN]-Ph H ??400.1
245. 3-Cl-Py-2yl 4-[C(CH 3) 2CH 2OMe]-Ph H ??419.2
246. 3-Cl-Py-2yl 4-isopr-Ph H ??375.1
247. 3-Cl-Py-2yl 4-(2-butyl)-Ph H ??389.1
248. 3-Cl-Py-2yl 4-Cl-Ph H ??367.0
249. 3-Cl-Py-2yl 3-Me，4-CF 3-Ph H ??415.1
250. 3-Cl-Py-2yl 4-[CH(CH 3)(CF 3)]-Ph H ??429.1
251. 3-Cl-Py-2yl 4-cyclopenta-Ph H ??401.1
252. 3-Cl-Py-2yl 4-cyclohexyl-Ph H ??415.2
253. Py-2yl 4-CF 3-Ph H ??367.1
254. Py-2yl 4-tBu-Ph H ??355.2
255. Py-2yl 4-isopr-Ph H ??341.2
256. Py-2yl 4-(2-butyl)-Ph H ??355.2
257. Py-2yl 4-cyclopenta-Ph H ??367.2
258. Py-2yl 4-cyclohexyl-Ph H ??381.2
259. 3-Cl-Py-2yl 6-CF 3-Py-3yl H ??402.1
260. 3-Cl-Py-2yl 4-tBu-Ph Me ??403.2
261. 3-Cl-Py-2yl 4-isopr-Ph Me ??389.1
262. 3-Cl-Py-2yl 4-CF 3-Ph Me ??415.1
263. 2-Cl-Ph 4-tBu-Ph H ??388.1
264. 2-Cl-Ph 4-isopr-Ph H ??374.1
265. 2-Cl-Ph 4-(2-butyl)-Ph H ??388.1
266. 3-CH 3-Py-2yl 4-CF 3-Ph H ??400.1
267. 3-CH 3-Py-2yl 4-tBu-Ph Me ??383.2
268. 3-CH 3-Py-2yl 4-isopr-Ph Me ??369.2
269. 3-CH 3-Py-2yl 4-CF 3-Ph Me
270. 3-CH 3-Py-2yl 4-(2-butyl)-Ph Me
271. 3-CH 3-Py-2yl 4-cyclopenta-Ph Me
272. 3-CF 3-Py-2yl 4-tBu-Ph Me
Chemical compound Ar 1 Ar 2 R 2 ?MS
273. 3-CF 3-Py-2yl ????4-isopr-Ph ????Me
274. 3-CF 3-Py-2yl ????4-CF 3-Ph ????Me
275. 3-CH 3-Py-2yl ????4-(CH 3-SO 2)-Ph ????Me
276. 3-CH 3-Py-2yl ????4-(CF 3-SO 2)-Ph ????Me
277. 3-CH 3-Py-2yl ????6-CF 3-Py-3yl ????Me
278. 3-CF 3-Py-2yl ????4-tBu-Ph ????H
279. 3-CF 3-Py-2yl ????4-isopr-Ph ????H
280. 3-CF 3-Py-2yl ????4-CF 3-Ph ????H
281. 3-CF 3-Py-2yl 4-cyclopenta-Ph ????H
282. 3-CF 3-Py-2yl 4-(morpholine-4yl-SO 2)-Ph ????H
283. 3-CH 3-Py-2yl 4-(morpholine-4yl-SO 2)-Ph ????Me
284. 3-CH 3-Py-2yl ????4-tBu-Ph Cyclobutyl ?423.2
285. 3-CH 3-Py-2yl ????4-isopr-Ph Cyclobutyl ?409.2
286. 3-CH 3-Py-2yl ????4-CF 3-Ph Cyclobutyl ?435.2
287. 3-CH 3-Py-2yl ????4-(CF 3-SO 2)-Ph Cyclobutyl ?499.1
288. 3-CH 3-Py-2yl ????5-CF 3-Py-2yl Cyclobutyl ?436.2
289. 3-CH 3-Py-2yl ????6-CF 3-Py-3yl Cyclobutyl
The added compound of preparation is recited in Table V.The abbreviation of using is as described in the preamble Table III.Variable position is shown in following structural formula:
Figure A0380245201901
Table V
Chemical compound Ar 1 Ar 2 R 2 ??MS
290. 3-CF 3-Py-2yl 4-tBu-Ph H ??423.2
291. 3-CF 3-Py-2yl 4-(tBu-NH-SO 2)-Ph H ??502.1
292. 3-CF 3-Py-2yl 6-tBu-Py-3yl H ??424.2
293. 3-CF 3-Py-2yl 4-CF 3-Ph Me ??449.1
294. 3-CF 3-Py-2yl 6-CF 3-Py-3yl Me
295. 3-CF 3-Py-2yl 5-CF 3-Py-2yl Me ??450.1
296. 3-Me-Py-2yl 4-CF 3-Ph H ??381.1
297. 3-Me-Py-2yl 6-CF 3-Py-3yl H ??382.1
298. 3-Me-Py-2yl 4-tBu-Ph H ??369.2
299. 3-Cl-Py-2yl 4-CF 3-Ph Me ??415.1
300. 3-Cl-Py-2yl 6-CF 3-Py-3yl Me ??416.1
301. 3-Cl-Py-2yl 4-(CF 3SO 2)-Ph Me ??479.0
302. 3-Cl-Py-2yl 4-CF 3-Ph H ??401.1
303. 3-Cl-Py-2yl 6-CF 3-Py-3yl H ??402.1
304. 3-Cl-Py-2yl 4-(CF 3SO 2)-Ph H ??465.0
305. 3-Cl-Py-2yl 6-tBu-Py-3yl Me ??404.2
306. 3-Cl-Py-2yl 4-tBu-Ph Me ??403.2
307. 3-CF 3-Py-2yl 4-isopr-Ph H ??409.2
Ar1-matrix, Het-matrix, and Ar2-matrix tabular lift can be by the multiple extra representative compounds of similar preceding method preparation.Chemical compound can form from any one-tenth of Ar1-matrix and Ar2-matrix is first via any Cheng Yuanyu of combination from the Het-matrix.For example deriving from the Ar1-matrix becomes unit 111 and derives from the combination acquisition part 111202 that the Het-matrix becomes unit 202.This part forms 111202312 with deriving from the becoming unit's 312 combinations of Ar2-matrix then, and it is (7-pyridine-2-base-quinazoline-4-yl)-(4-trifluoromethyl-phenyl)-amine.
Figure A0380245201911
The Ar1-matrix
The Het-matrix
The Ar2-matrix
Embodiment 2
The preparation of representative compounds
Present embodiment illustrates the preparation of the representational 2-aminoalkyl-quinazoline that is substituted-4-ylamine analogues.
A.[2-Pyrrolizidine-1-ylmethyl-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-(4-trifluoro Methyl-phenyl)-amine (chemical compound 308)
2-right-tolyl-3-trifluoromethyl-pyridine
Figure A0380245201941
To 2-chloro-3-(trifluoromethyl)-pyridine (70.1 mM), right-tolyl dihydroxy boric acid (70.6 mM), and 2M sodium carbonate (175.0 mM) at dimethyl ether (DME; 200 milliliters) through in the mixture of degasification, under nitrogen, add Pd (PPh 3) 4(2.8 mM).Mixture concentrates, with ethyl acetate extraction 80 ℃ of stirred overnight.With sodium sulfate dehydration, through vacuum concentration, by the silica gel liner obtain 2-right-tolyl-3-trifluoromethyl-pyridine.
2. 2-(4-methyl-3-nitro-phenyl)-3-(trifluoromethyl)-pyridine
Figure A0380245201942
To 2-right-tolyl-3-trifluoromethyl-pyridine (8.4 mM) careful fuming nitric aicd (2 milliliters) that adds in the solution of sulphuric acid (6 milliliters).Mixture was stirring at room 60 minutes.To frozen water (30 milliliters), with ethyl acetate extraction, with the neutralization of 1N sodium hydroxide, with the sodium sulfate dehydration, and vacuum concentration obtains 2-(4-methyl-3-nitro-phenyl)-3-(trifluoromethyl)-pyridine to mixture.
3. 2-nitro-4-(3-trifluoromethyl-pyridine-2-yl)-benzoic acid
, in the solution of the mixture of pyridine (10 milliliters) and water (5 milliliters), be divided into several parts and add KMnO to 2-(4-methyl-3-nitro-phenyl)-3-(trifluoromethyl)-pyridine (7.1 mM) 4(25.3 mM).Mixture stirred 4 hours at 110 ℃, added 25.3 mM KMnO with 10 ml waters again then 4Mixture is 110 ℃ of stirred overnight.Be cooled to room temperature, filter by C ore deposit (celite) liner.Filtrate is through vacuum concentration, with the water dilution and with the ethyl acetate solution washing.Aqueous solution obtains 2-nitro-4-(3-trifluoromethyl-pyridine-2-yl)-benzoic acid with neutralization of 2N hydrochloric acid and collecting precipitation.
4. 2-nitro-4-(3-trifluoromethyl-pyridine-2-yl)-benzyl amide
2-amino-4-(3-trifluoromethyl-pyridine-2-yl)-benzoic acid (25 gram) and SOCl 2The mixture of (50 milliliters) refluxed 4 hours and concentrated.Residue is dissolved in dichloromethane (DCM), with ice-water bath cooling, NH 3Gas was by solution 30 minutes, stirring at room 15 minutes.Concentrate to reach and obtain 2-nitro-4-(3-trifluoromethyl-pyridine-2-yl)-benzyl amide with water washing.
5. 2-amino-4-(3-trifluoromethyl-pyridine-2-yl)-benzyl amide
Use 50psi hydrogen and 100 milligrams of 10%Pd/C at ethanol hydrogenation 2-nitro-4-(3-trifluoromethyl-pyridine-2-yl)-benzyl amide (1.0 grams, 0.0032 mole).After 16 hours, mixture filters through the C ore deposit, under reduced pressure concentrates and obtains 2-amino-4-(3-trifluoromethyl-pyridine-2-yl)-benzyl amide, is solid.
6. 2-chloromethyl-7-(3-trifluoromethyl-pyridine-2-yl)-3H-quinazoline-4-one
Figure A0380245201961
2-amino-4-(3-trifluoromethyl-pyridine-2-yl)-benzyl amide (100 milligrams, 0.356 mM) is at 2-chloro-1,1, and the solution of 1-trimethoxy-ethane (138 ℃ of bp) was 130 ℃ of heating 4 hours.Mixture under reduced pressure concentrates and obtains 2-chloromethyl-7-(3-trifluoromethyl-pyridine-2-yl)-3H-quinazoline-4-one, is oil, crystallization when placing.
7. 4-chloro-2-chloromethyl-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline
2-chloromethyl-7-(3-trifluoromethyl-pyridine-2-yl)-3H-quinazoline-4-one (deriving from previous reaction) and POCl 3Mixture refluxed 16 hours.Cooling mixture also under reduced pressure concentrates.The residue branch is dissolved in ethyl acetate and saturated sodium bicarbonate solution.The ethyl acetate part is with extra sodium bicarbonate washing, and dehydration (sodium sulfate) also under reduced pressure concentrates then.The brown residue filters through two inches silica gel (1: 1 ethyl acetate/hexane class eluant), under reduced pressure concentrates to obtain 4-chloro-2-chloromethyl-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline.
8.[2-chloromethyl-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine
4-chloro-2-chloromethyl-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline (42 milligrams, 0.117 mM) and 4-trifluoromethyl-aniline (19 milligrams, 0.117 mM) heated 4 hours at 75 ℃ at the mixture of isopropyl alcohol (1 milliliter).Cooling mixture, precipitation then obtain [2-chloromethyl-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine with the ether washing with washed with isopropyl alcohol, are a hydrochlorate.
9.[2-Pyrrolizidine-1-ylmethyl-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine
[2-chloromethyl-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine HCl (30 milligrams, 0.058 mM) heated 1 hour at 100 ℃ at the solution of Pyrrolizidine (1 milliliter).Under reduced pressure remove excessive Pyrrolizidine, the residue branch is dissolved in ethyl acetate and 10% sodium bicarbonate solution.Ethyl acetate layer obtains [2-Pyrrolizidine-1-ylmethyl-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine through dehydration (sodium sulfate) and under reduced pressure concentrated, is foams.Mass spectrum 517.2.
B.[2-(2,6-dimethyl-morpholine-4-ylmethyl)-7-(2-trifluoromethyl-phenyl)-pyrido [4,3-d] is phonetic Pyridine-4-yl]-(4-trifluoromethyl-phenyl)-amine (suitable) (chemical compound 309)
1. 4-hydroxyl-6-(2-trifluoromethyl-phenyl)-niacin ethyl ester
Figure A0380245201972
To dissolve two (TMS) amide lithiums (LiHMDS) (34 grams, 0.20 mole) and, under nitrogen atmosphere, be cooled to-70 ℃ in anhydrous THF (150 milliliters).Add 4-dimethylamino-3-ethyoxyl-Ding-3-alkene-2-ketone (15 grams, 0.081 mole; With reference to heterocyclic chemistry periodical (1987) 24:1669) and 2-(trifluoromethyl) Benzenecarbonyl chloride. (20.0 gram, 0.097 mole) at THF (50 milliliters) to 10 fens clock times of solution experience.Remove cooling bath and stirred 10 minutes.Add ammonium acetate (10 gram) and acetic acid (200 milliliters) to reactant mixture, THF is removed in distillation under reduced pressure.Mixture cools off, and adds water (250 milliliters) and dichloromethane (250 milliliters) 60-65 ℃ of heating 18 hours.The separate dichloromethane layer, water layer is with dichloromethane (2 * each 250 milliliters) extracting twice.Combination dichloromethane extract, dehydration (magnesium sulfate) and evaporation.By silica gel column chromatography art purification, obtain 4-hydroxyl-6-(2-trifluoromethyl-phenyl)-niacin ethyl ester and be yellow solid.
2. 4-chloro-6-(2-trifluoromethyl-phenyl)-niacin ethyl ester
4-hydroxyl-6-(2-trifluoromethyl-phenyl)-niacin ethyl ester (9.0 grams, 0.029 mole) heated 2 hours at 110 ℃ at the mixture of phosphoryl chloride phosphorus oxychloride (22 gram).The evaporative removal phosphoryl chloride phosphorus oxychloride, (100 gram) on the rocks, the then careful saturated sodium bicarbonate that adds.With ethyl acetate extraction, dehydration (magnesium sulfate), and evaporation acquisition 4-chloro-6-(2-trifluoromethyl-phenyl)-niacin ethyl ester are brown oil.
3. 4-amino-6-(2-trifluoromethyl-phenyl)-nicotianamine
Figure A0380245201982
The mixture of 4-chloro-6-(2-trifluoromethyl-phenyl)-niacin ethyl ester (5.2 gram) and 28% aqueous ammonium hydroxide (100 milliliters) was 350 milliliters of resealable pressurizing vessel internal heating 60 hours.Cooling, with ethyl acetate (3 * each 100 milliliters) extraction, dehydration (magnesium sulfate), and evaporation obtains crude product.By silica gel column chromatography art purification, obtain 4-amino-6-(2-trifluoromethyl-phenyl)-nicotianamine, be solid.
4. 2-(2,6-dimethyl-morpholine-4-ylmethyl)-7-(2-trifluoromethyl-phenyl)-pyrido [4,3-d] pyrimidine-4-alcohol
Figure A0380245201991
4-amino-6-(2-trifluoromethyl-phenyl)-nicotianamine (1 gram, 3.5 mMs), (2,6-dimethyl-morpholine-4-yl)-ethyl acetate (2.85 grams, 14 mMs), sodium acetate (5.0 equivalent) heated 20 hours at the solution of ethanol (10 milliliters).After the cooling, reactant mixture under reduced pressure concentrates, and mixture with ethyl acetate (3 * each 25 milliliters) extraction, washes twice with water (each 25 milliliters) with water (25 milliliters) dilution then, dewaters with magnesium sulfate.Evaporation obtains 2-(2,6-dimethyl-morpholine-4-ylmethyl)-7-(2-trifluoromethyl-phenyl)-pyrido [4,3-d] pyrimidine-4-alcohol by tomography purification rapidly.
5. 4-chloro-2-(2,6-dimethyl-morpholine-4-ylmethyl)-7-(2-trifluoromethyl-phenyl)-pyrido [4,3-d] pyrimidine
Figure A0380245201992
2-(2,6-dimethyl-morpholine-4-ylmethyl)-7-(2-trifluoromethyl-phenyl)-pyrido [4,3-d] pyrimidine-4-alcohol (0.6 gram), 2,6-lutidines (0.62 gram) and phosphoryl chloride phosphorus oxychloride (1.1 gram) refluxed 20 hours in the mixture of chloroform (15 milliliters).Cooling mixture under reduced pressure concentrates.The residue branch is dissolved in ethyl acetate and saturated sodium bicarbonate solution.With extra sodium bicarbonate washing ethyl acetate, then through dehydration (sodium sulfate) and under reduced pressure concentrated.The brown residue filters by two inches silica gel (1: 1 ethyl acetate/hexane class eluant), under reduced pressure concentrates, and obtains 4-chloro-2-(2,6-dimethyl-morpholine-4-ylmethyl)-7-(2-trifluoromethyl-phenyl)-pyrido [4,3-d] pyrimidine.
(6.[2-2,6-dimethyl-morpholine-4-ylmethyl)-7-(2-trifluoromethyl-phenyl)-pyrido [4,3-d] pyrimidine-4-yl]-(4-trifluoromethyl-phenyl)-amine (suitable)
Figure A0380245202001
4-chloro-2-(2,6-dimethyl-morpholine-4-ylmethyl)-7-(2-trifluoromethyl-phenyl)-pyrido [4,3-d] pyrimidine (43.7 milligrams, 0.1 mM) and 4-trifluoromethyl-aniline (16.1 milligrams, 0.1 mM) at the mixture of acetonitrile (1 milliliter) 80 ℃ of heating 24 hours.Mixture is through cooling, and precipitation obtains 4-chloro-2-(2,6-dimethyl-morpholine-4-ylmethyl)-7-(2-trifluoromethyl-phenyl)-pyrido [4,3-d] pyrimidine with the ether washing, is a hydrochlorate.Mass spectrum 561.2.
C.[2-morpholine-4-ylmethyl-7-(3-trifluoromethyl-pyridine-2-yl)-pyrido [3,2-a] pyrimidine-4- Base]-(4-trifluoromethyl-phenyl)-amine (chemical compound 310)
1. 6 '-methoxyl group-3-trifluoromethyl-[2,3 '] bipyridyl
With 2-chloro-3-5-flumethiazine (37 grams, 0.2 2-methoxypyridine-5-dihydroxy boric acid (32 grams mole),, 0.21 mole), tetrakis triphenylphosphine palladium (O) (9 grams, 7 mMs) and 2M potassium carbonate (150 milliliters) heated 8 hours at 90 ℃ under nitrogen atmosphere at the mixture of toluene (500 milliliters).Reaction mixture and be separated into each layer.Water layer is with ethyl acetate (2 * 250 milliliters) extraction, and the combination organic layer is with 4M sodium hydroxide (250 milliliters), water (250 milliliters) and saline solution (250 milliliters) washing.Dehydration (magnesium sulfate) and under reduced pressure concentrated.Oil by tomography purification rapidly, obtains title compound (48.2 grams, 95%) at silica gel (50% ether/50% hexane), is water white oil.
2. 3-Trifluoromethyl-1 ' H-[2,3 '] bipyridyl-6 '-ketone
Figure A0380245202003
6 '-methoxyl group-3-trifluoromethyl-[2,3 '] bipyridyl (41 gram, 0.16 mole) was 30% hydrogen bromide/acetic acid (100 milliliters) reflux 1 hour.Cooling mixture and filtration, precipitation is washed with ether (100 milliliters).Precipitation is passed to 10M sodium hydroxide (500 milliliters) and stirred 1 hour, and solution is pH7 with salt acid treatment to solution.Collect white solid and air-dry acquisition title compound (36 grams, 93%) by filtering, solid is white in color.
3. 5 '-nitro-3-Trifluoromethyl-1 ' H-[2,3 '] bipyridyl-6 '-ketone
Figure A0380245202011
To the 3-Trifluoromethyl-1 ' H-[2,3 '] bipyridyl-6 '-ketone (25 gram, 0.1 mole) is in the solution of concentrated sulphuric acid (100 milliliters), at 0 ℃ of solution that dropwise adds 10 milliliters of fuming nitric aicd (35 milliliters) and concentrated sulphuric acids.Reactant mixture be heated to 70 ℃ 1 hour, cool off and be poured onto on the ice (500 milliliters).Mixture reach after filtration filtrate with the 10M naoh treatment to solution at pH4-5.By filtering collecting precipitation and air-dry, obtain title compound (26.2 grams, 92%), solid is white in color.
4. 6 '-chloro-5 '-nitro-3-trifluoromethyl-[2,3 '] bipyridyl
Figure A0380245202012
With 5 '-nitro-3-Trifluoromethyl-1 ' H-[2,3 '] the mixture reflux of bipyridyl-6 '-ketone (25 gram, 0.088 mole), sulphinyl chlorine (300 milliliters) and DMF (3 milliliters) 4 hours.Remove volatile matter by rotary evaporation, the residue branch is dissolved in ethyl acetate (350 milliliters) and saturated sodium bicarbonate solution (250 milliliters).Water layer reuse ethyl acetate (250 milliliters) extraction, the combination organic layer washs with saline solution (250 milliliters).Dehydration (magnesium sulfate) and under reduced pressure concentrated obtains title compound (25 grams, 93%), is yellow oil.
5. 6 '-chloro-3-trifluoromethyl-[2,3 '] bipyridyl-5 '-Ji amine
In the solution of ethanol (300 milliliters) and water (50 milliliters), add iron powder (45 grams, 0.82 mole) to 6 '-chloro-5 '-nitro-3-trifluoromethyl-[2,3 '] bipyridyl (25 grams, 0.082 mole) and calcium chloride (11 grams, 0.1 mole).Solution reflux 1.5 hours, cooling is filtered through the C ore deposit.Mixture under reduced pressure concentrates, and is dissolved in ethyl acetate (300 milliliters) once again and washs with saline solution (200 milliliters).Solution under reduced pressure concentrates, and by flash chromatography art purification, obtains title compound (19 grams, 85%) at silica gel (50% ether/50% hexane), is the lark solid.
6. 3-amino-5-[3-(trifluoromethyl) (2-pyridine radicals)] pyridine-2-carboxylic acid amides
6 '-chloro-3-trifluoromethyl-[2,3 '] bipyridyl-5 '-Ji amine (25 grams, 0.091 mole), zinc cyanide (6.75 grams, 0.058 mole), three (dibenzalacetones), two-palladium (are also referred to as and are " pd 2(dba) 3"; 2.63 gram, 2.86 mMs), 1,1 '-two (diphenylphosphino) halotrichite (is also referred to as and is " DPPF "; 3.16 gram, 5.72 mMs) the solution of DMF (250 milliliters) and water (2.5 milliliters) under nitrogen atmosphere 120 ℃ of heating 1 hour.Add water (30 milliliters), solution is finished hydrolysis 120 ℃ of heating 4 hours again.Solution is cooled to 0 ℃, adds saturated ammonium chloride (200 milliliters), water (200 milliliters) and dense ammonium hydroxide (50 milliliters) solution., filter and remove yellow mercury oxide after 1 hour 0 ℃ of stirring, with water (200 milliliters) and the washing of 1: 1 mixture (200 milliliters) of ether-hexane.Solid obtains (23 grams, 90%) title compound in air dehydration vacuum drying oven dehydration then.
7. 2-(chloromethyl)-7-[3-(trifluoromethyl) (2-pyridine radicals)]-3-pyridinium hydroxide [3,2-d] pyrimidin-4-one also
Figure A0380245202031
3-amino-5-[3-(trifluoromethyl) (2-pyridine radicals)] pyridine-2-carboxylic acid amides (23 grams, 81.5 mMs) and 2-chloro-1,1, the solution of 1-trimethoxy-ethane (250 milliliters) was 130 ℃ of heating 1 hour.By the evaporative removal volatile matter, abrasive solid (50% ether/50% hexane) obtains title compound, is light brown solid (21 grams, 76%).
8. 2-(morpholine-4-ylmethyl)-7-[3-(trifluoromethyl) (2-pyridine radicals)]-3-pyridinium hydroxide [3,2-d] pyrimidin-4-one also
Figure A0380245202032
With 2-(chloromethyl)-7-[3-(trifluoromethyl) (2-pyridine radicals)]-also [3,2-d] pyrimidin-4-one (20 grams, 0.058 mole), morpholine (15.66 grams, 0.18 mole) heated 12 hours at 80 ℃ at the solution of acetonitrile (500 milliliters) the 3-pyridinium hydroxide.Evaporative removal solution, residue branch are dissolved in ethyl acetate (500 milliliters) and saturated sodium carbonate solution (500 milliliters).Water layer is again with ethyl acetate (250 milliliters) extraction, and the combination organic layer washs with saline solution (500 milliliters).Dehydration (magnesium sulfate) under reduced pressure concentrates, and obtains title compound (18.8 grams, 83%) and is brown solid.
9. 4-({ chloro-7-[3-(trifluoromethyl) (2-pyridine radicals)] pyrido [3,2-d] pyrimidine-2-base } methyl)-methyl morpholine
Figure A0380245202033
2-(morpholine-4-ylmethyl)-7-[3-(trifluoromethyl) (2-pyridine radicals)]-3-pyridinium hydroxide also [3,2-d] pyrimidin-4-one (11.73 grams, 0.03 mole), phosphoryl chloride phosphorus oxychloride (13.8 grams, 0.09 mole) and 2,6-lutidines (9.63 grams, 0.09 mole) heated 12 hours at 60 ℃ at the solution of chloroform (500 milliliters).Evaporative removal solvent, residue branch are dissolved in ethyl acetate (500 milliliters) and saturated sodium carbonate solution (500 milliliters).Water layer is again with ethyl acetate (250 milliliters) extraction, with saline solution (500 milliliters) washing combination organic layer.Dehydration (magnesium sulfate) and under reduced pressure concentrated obtains title compound (11.5 grams, 94%), is brown solid.
10.[2-morpholine-4-ylmethyl-7-(3-trifluoromethyl-pyridine-2-yl)-pyrido [3,2-a] pyrimidine-4-yl]-(4-trifluoromethyl-phenyl)-amine
4-(chloro-7-[3-(trifluoromethyl) (2-pyridine radicals)] pyrido [3,2-d] pyrimidine-2-base } methyl)-methyl morpholine (12.2 grams, 0.03 mole), 4-(trifluoromethyl) aniline (4.8 grams, 0.03 mole) heated 12 hours at 80 ℃ at the solution of acetonitrile (500 milliliters).Evaporative removal solution, residue branch are dissolved in ethyl acetate (500 milliliters) and saturated sodium carbonate solution (500 milliliters).Water layer is again with ethyl acetate (2 * 250 milliliters) extraction, and the combination organic layer washs with saline solution (500 milliliters).Dehydration (magnesium sulfate) and under reduced pressure concentrated.Residue obtains title compound (12.5 grams, 78%) at silica gel (90% ether/10% hexane is 100% ether then) purification.Mass spectrum 534.2.
D.[2-(2-Pyrrolizidine-1-base-ethyl)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-(4- Trifluoromethyl-phenyl)-amine (chemical compound 311)
1. 3-benzyloxy-propanoic acid
Figure A0380245202042
Be divided into aliquot sodium hydride (2.22 grams, 60% at the mineral oil dispersion liquid, 55.4 mMs) is added to benzylalcohol (4.0 grams, 37 mMs) cold (0 ℃) solution at toluene (100 milliliters).3-ethyl bromide (8.0 grams, 44 mMs) dropwise is added into mixture, and gained solution is warmed to room temperature and stirred 1 hour.Reaction is by adding the water quenching till whole foamings stop.Mixture is with ethyl acetate (100 milliliters) dilution, with water (100 milliliters) and saline solution (100 milliliters) extraction.Organic extract dewaters with sodium sulfate, under reduced pressure removes solvent, obtains the crude product ester, is clarified oil.Oil is dissolved in methanol (20 milliliters) and 6N sodium hydroxide (20 milliliters), stirs 1 hour.Mixture (about 20 milliliters) dilutes with water (20 milliliters) through concentrating.Aqueous mixture is washed once with dichloromethane (40 milliliters).Water is with the concentrated hydrochloric acid acidify, and with ethyl acetate (3 * 50 milliliters) extraction, the combination acetic acid ethyl ester extract dewaters with sodium sulfate.Under reduced pressure remove solvent, obtain title compound, be clarified oil (2.28 grams, 34.0%), when placing, solidify.
2. 2-(2-benzyloxy-ethyl)-7-(3-trifluoromethyl-pyridine-2-yl)-3H-quinazoline-4-one
Figure A0380245202051
3-benzyloxy-propanoic acid (1.66 grams, 9.19 mMs) is cooled to 0 ℃ at the solution of hexane class (40 milliliters), dropwise adds oxalyl chloride (3.50 grams, 27.6 mMs).After interpolation is finished, add DMF (2), the gained mixture stirred 1 hour.Under reduced pressure remove solvent, the crude product acyl chlorides is dissolved in anhydrous THF (20 milliliters).In minute uncork, dissolve 2-amino-4-(3-trifluoromethyl-pyridine-2-yl)-benzyl amide (2.35 grams, 8.37 mMs) at anhydrous THF (40 milliliters) and pyridine (0.727 gram, 9.19 mMs), and be cooled to 0 ℃.Contain the crude product solution of acid chloride and dropwise be added into second solution.Allow mixture be warmed to room temperature and stirred 1 hour.10% sodium hydroxide (aqueous solution) (20 milliliters) is added into mixture, solution stirring 1 hour.Enriched mixture (about 20 milliliters) is with water (20 milliliters) dilution, with the concentrated hydrochloric acid acidify.Gained solution extracts with ethyl acetate (3 * 50 milliliters).The combination organic extract reaches with the saline solution washing and dewaters with sodium sulfate.Under reduced pressure remove solvent, obtain title compound, the solid that is white in color (3.24 grams, 82.9%).
3. 2-(benzyloxy-ethyl)-4-chloro-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline
Figure A0380245202052
2-(2-benzyloxy-ethyl)-7-(3-trifluoromethyl-pyridine-2-yl)-3H-quinazoline-4-one (3.24 grams, 7.62 mMs) is dissolved in chloroform (40 milliliters) and 2,6-lutidines (2.45 grams, 22.9 mMs).Dropwise add phosphoryl chloride phosphorus oxychloride (1.77 milliliters, 19.0 mMs), gained solution reflux 18 hours.Cooling solution is under reduced pressure removed solvent.Crude product residue branch is dissolved in ethyl acetate (200 milliliters) and saturated sodium bicarbonate (aqueous solution) (200 milliliters).Remove organic facies, water extracts with ethyl acetate (200 milliliters).Make up two kinds of extracts,, dewater with sodium sulfate with saline solution (200 milliliters) washing.Remove solvent, obtain title compound, be light brown solid (2.47 grams, 73.1%).
(4.[2-2-benzyloxy-ethyl)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine
Figure A0380245202061
2-(benzyloxy-ethyl)-4-chloro-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline (2.47 grams, 5.57 mMs) is dissolved in the solution of acetonitrile (50 milliliters) and 4-trifluoromethyl-aniline (0.986 gram, 6.12 mMs).Mixture heated to 80 ℃ 2 hours formation white precipitates.Solution is in the ice bath cooling and add ether (25 milliliters).Filter and remove white precipitate, vacuum dehydration obtains title compound, is a hydrochlorate (2.96 grams, 87.8%).
5. 2-[4-(4-trifluoromethyl-phenyl amino)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-2-yl]-ethanol
[2-(2-benzyloxy-ethyl)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine hydrochlorate (2.96 grams, 4.89 mMs) is dissolved in methanol (1 50 milliliters), and adds 10% Pd/C (200 milligrams).Mixture at 60 ℃ 50p.s.i. hydrogenation 8 hours.Mixture filters fast through the C ore deposit, and C ore deposit filter cake washs with hot methanol (200 milliliters).Under reduced pressure remove solvent, obtain title compound one hydrochlorate, the solid that is white in color (1.75 grams, 69.5%).
(6.[2-2-chloro-ethyl)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine
2-[4-(4-trifluoromethyl-phenyl amino)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-2-yl]-ethylate hydrochlorate (1.54 gram, 2.99 mMs) is dissolved in sulphinyl chlorine (20 milliliters), be heated to 60 ℃ 1 hour.Under reduced pressure remove excessive sulphinyl chlorine, residue uses ether to grind, and obtains title compound one hydrochlorate, is light brown solid (1.48 grams, 92.8%).
(7.[2-2-Pyrrolizidine-1-base-ethyl)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine
Figure A0380245202072
With (20 milligrams of [2-(2-chloro-ethyl)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine hydrochlorates, 0.0375 mM) be dissolved in acetonitrile/10% diisopropyl ethyl amine (0.187 milliliter), add the 0.2N Pyrrolizidine at acetonitrile solution (0.281 milliliter).Mixture was 70 ℃ of heating 18 hours.Under reduced pressure remove solvent, the crude product mixture branch is dissolved in ethyl acetate (1 milliliter) and 1N sodium hydroxide.Remove organic extract, water extracts with ethyl acetate (1 milliliter) once again.The combination organic extract filters through fritter silica gel liner, with washing with acetone, obtains title compound, is light brown solid (18 milligrams, 90%).
E.[2-(3-morpholine-4-base-propyl group)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-(4-three Methyl fluoride-phenyl)-amine hydrochlorate (chemical compound 313)
1. 3-[4-hydroxyl-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-2-yl]-ethyl propionate
Figure A0380245202081
To 2-amino-4-(3-trifluoromethyl-pyridine-2-yl)-benzyl amide (0.5 mM) and pyridine (0.55 mM) in the solution of THF (5 milliliters), add 3-chloroformyl-ethyl propionate chloride (0.55 mM).Mixture adds 20 milliliter of 21% sodium acetate at ethanol stirring at room 20 minutes, stirs 30 minutes at 50 ℃.Concentrate, add water, filter, be acidified to pH6, collecting precipitation obtains 3-[4-hydroxyl-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-2-yl]-ethyl propionate.
2. 3-[4-chloro-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-2-yl]-ethyl propionate
Figure A0380245202082
Use similar aforementioned program, by 3-[4-hydroxyl-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-2-yl]-ethyl propionate prepares 3-[4-chloro-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-2-yl]-ethyl propionate.
3. 3-[4-(4-trifluoromethyl-phenyl amino)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-2-yl]-ethyl propionate
Figure A0380245202091
Use similar aforementioned program, by 3-[4-chloro-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-2-yl]-ethyl propionate prepares 3-[4-(4-trifluoromethyl-phenyl amino)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-2-yl]-ethyl propionate.
4. 3-[4-(4-trifluoromethyl-phenyl amino)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-2-yl]-propanoic acid
Figure A0380245202092
To 3-[4-(4-trifluoromethyl-phenyl amino)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-2-yl]-ethyl propionate (0.5 mM) in the mixture of THF (20 milliliters) and water (20 milliliters), add Lithium hydrate (1.5 mM).Mixture stirred 2 hours at 60 ℃.Concentrate, add water, with the ether extraction, water layer is acidified to pH4-5, with ethyl acetate extraction and concentrated, obtains 3-[4-(4-trifluoromethyl-phenyl amino)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-2-yl]-propanoic acid.
5. 1-morpholine-4-base-3-[4-(4-trifluoromethyl-phenyl amino)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-2-yl]-third-1-ketone (chemical compound 312)
Figure A0380245202093
To 3-[4-(4-trifluoromethyl-phenyl amino)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-2-yl]-propanoic acid (0.5 mM) and triethylamine (0.5 mM) in the solution of DMF (10 milliliters), add benzotriazole-1-base-oxygen base-three (dimethylamino) phosphonium hexafluorophosphate (BOP; 0.5 mM).Mixture was mixed under room temperature is stirred 18 hours, with the water dilution, with ethyl acetate extraction, washed with saline solution.Concentrate and obtain 1-morpholine-4-base-3-[4-(4-trifluoromethyl-phenyl amino)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-2-yl]-third-1-ketone.Mass spectrum 575.2.
(6.[2-3-morpholine-4-base-propyl group)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine hydrochlorate (chemical compound 313)
To 1-morpholine-4-base-3-[4-(4-trifluoromethyl-phenyl amino)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-2-yl]-third-1-ketone (0.14 mM) adds LAH (0.67 mM) in the solution of THF (20 milliliters).Mixture at room temperature stirred 6 hours, with 10% sodium hydroxide quenching, with ethyl acetate extraction, with sodium sulfate dehydration and adding hydrochloric acid-ethyl acetate.Collecting precipitation obtains [2-(3-morpholine-4-base-propyl group)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine hydrochlorate.Mass spectrum 561.2.
F.4-trifluoromethyl-[2-(2 6-thebaine-4-ylmethyl)-7-(2-trifluoromethyl)- Quinazoline-4-yl]-amine (chemical compound 314)
1. 7-bromo-2-chloromethyl-3H-quinazoline-4-one
Figure A0380245202102
With 2-amino-4-bromobenzyl amide (27 grams, 0.13 mole; With reference to Joshi and Chaudhari (1987) India chemical periodical, the B chapters and sections, 26B (6): 602-4) at 2-chloro-1,1, the solution in the 1-trimethoxy-ethane (50 milliliters) refluxed 30 minutes, big precipitation occurred in this section period.The evaporative removal mixture uses ether to grind fully, collects 28 gram 7-bromo-2-chloromethyl-3H-quinazoline-4-ones, and solid is white in color.
2. 7-bromo-4-chloro-2-chloromethyl quinazoline
With 7-bromo-2-chloromethyl-3H-quinazoline-4-one (5 grams, 18.2 mMs), 2,6-lutidines (5 gram) and phosphoryl chloride phosphorus oxychloride (5 milliliters) are 1, and the mixture of 2-dimethoxy-ethane (500 milliliters) was 80 ℃ of heating 16 hours.Mixture is cooled to room temperature, and the evaporative removal mixture reaches with water washing with the ether dilution then fully.Solvent obtains 7-bromo-4-chloro-2-chloromethyl quinazoline (3.5 gram) and is yellow solid through dehydration (sodium sulfate) and evaporation ether.
3. 7-bromo-2-(chloromethyl quinazoline-4-yl)-(4-trifluoromethyl)-amine
7-bromo-4-chloro-2-chloromethyl quinazoline (1168 milligrams, 4.0 mMs) and 4-(trifluoromethyl) aniline (644 milligrams, 4.0 mMs) heated 16 hours at 60 ℃ at the mixture of chloroform (50 milliliters).Cooling and collecting precipitation product 7-bromo-2-(chloromethyl quinazoline-4-yl)-(4-trifluoromethyl)-amine (1021 milligrams) are hydrochlorate.
4.[7-bromo-2-(suitable-2,6-thebaine-4-ylmethyl)-quinazoline-4-yl]-4-(trifluoromethyl)-amine
(416 milligrams of 7-bromo-2-(chloromethyl quinazoline-4-yl)-(4-trifluoromethyl)-amine, 1.0 mM), suitable-2, (150 milligrams of 6-thebaines, 1.3 mM) and (202 milligrams of triethylamines, 2.0 mM) the mixture heated of N,N-dimethylacetamide (7 milliliters) 1 hour.Be cooled to room temperature, with ethyl acetate (50 milliliters) dilution, to wash (each 25 milliliters) 4 times.Dehydration (sodium sulfate) and evaporation.Use ether to grind to obtain [7-bromo-2-(suitable-2,6-thebaine-4-ylmethyl)-quinazoline-4-yl]-4-(trifluoromethyl)-amine (430 milligrams are yellow solid).
(5.[2-suitable-2,6-thebaine-4-base oxygen ylmethyl)-7-(2-trifluoromethyl)-quinazoline-4-yl]-(4-trifluoromethyl)-amine
Under nitrogen, [7-bromo-2-(suitable-2,6-thebaine-4-ylmethyl)-quinazoline-4-yl]-4-(trifluoromethyl)-amine (75 milligrams, 0.15 mM), (45 milligrams of 2-(trifluoromethyl) dihydroxy boric acid, 0.23 mM), tetrakis triphenylphosphine palladium (O) (21 milligrams, 0.018 mM), the 2M sodium carbonate is at water (1 milliliter), and 1, the mixture of 2-dimethoxy-ethane (5 milliliters) was 60 ℃ of heating 16 hours.Mixture is cooled to room temperature, with the ethyl acetate dilution and to wash (each 10 milliliters) twice.Organic layer is through dehydration (sodium sulfate) and evaporation.(9: 1 dichloromethane: methanol) purification obtains [2-(suitable-2,6-thebaine-4-base oxygen ylmethyl)-7-(2-trifluoromethyl)-quinazoline-4-yl]-(4-trifluoromethyl)-amine (112 milligrams), is yellow solid by preparation property TLC.Mass spectrum 560.2.
G.[7-(3-methyl-pyridine-2-yl)-2-Pyrrolizidine-1-ylmethyl-pyrido [3,2-d] pyrimidine-4- Base]-(4-trifluoromethyl-phenyl)-amine (chemical compound 315)
1. 5-bromo-3-nitropyridine-2-formonitrile HCN
2-amino-5-bromo-3-nitropyridine (2.18 gram, 10 mMs), Cupricin. (1.33 grams, 15 mMs) and nitrous acid uncle-butyl ester (2.0 milliliters, 15 mMs) the solution of acetonitrile (50 milliliters) be heated to 60 ℃ 2 hours.Solution divides to be dissolved in ethyl acetate (100 milliliters) and saturated sodium bicarbonate aqueous solution (100 milliliters) through cooling.Aqueous solution,, dewaters in (magnesium sulfate) and evaporation with saline solution (100 milliliters) washing with water (100 milliliters) washing with ethyl acetate (2 * 50 milliliters) extraction.Solid by flash chromatography art purification, obtains title compound at silica gel (25% ether/75% hexane), is lark solid (934 milligrams, 41%).
2. 5-(3-methyl (2-pyridine radicals)-3-nitropyridine-2-formonitrile HCN
5-bromo-3-nitropyridine-2-formonitrile HCN (228 milligrams, 1.0 mMs), tetrakis triphenylphosphine palladium (O) (15 milligrams), 3-methyl-2-pyridine radicals zinc bromide (0.5M is at THF, 3 milliliters, 1.5 mMs) the solution of THF (5 milliliters) be heated to 60 ℃ 2 hours.Solution is through cooling, and branch is dissolved in ethyl acetate (10 milliliters) and saturated aqueous sodium bicarbonate (10 milliliters).Aqueous solution is with ethyl acetate (2 * 15 milliliters) extraction, and with water (10 milliliters), saline solution (10 milliliters) washing, dehydration (magnesium sulfate) and evaporation obtain title compound, are lark solid (211 milligrams, 88%).
3. 3-amino-5-(3-methyl (2-pyridine radicals)) pyridine-2-carboxylic acid amides
Figure A0380245202133
(3-methyl (2-pyridine radicals)-3-nitropyridine-2-formonitrile HCN (1 gram, 4.1 mMs), ferrum (2.3 grams, 40 mMs) and calcium chloride (560 milligrams, 5 mMs) were the solution reflux of ethanol (15 milliliters) and water (4 milliliters) 1 hour for 5-.Mixture filters through the C ore deposit and washs with ethyl acetate through cooling.Filtrate is through evaporation, and residue is dissolved in ethyl acetate once again, and then with the saline solution washing, dehydration (magnesium sulfate) and evaporation obtain title compound, are lark solid (880 milligrams, 94%) with water.
(4.[7-3-methyl-pyridine-2-yl)-2-Pyrrolizidine-1-ylmethyl-pyrido [3,2-d] pyrimidine-4-yl]-(4-trifluoromethyl-phenyl)-amine
Title compound is with similar preparation [2-Pyrrolizidine-1-ylmethyl-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine (the embodiment 2.A that is used for, step 6 is to 9) mode used, by 3-amino-5-(3-methyl (2-pyridine radicals)) pyridine-2-carboxylic acid amides preparation.
H. other representational 2-aminoalkyl-quinazoline that is substituted-4-ylamine analogues
Those skilled in the art should understand can change starting material, and adopts additional step, makes other chemical compound that the present invention is contained.The chemical compound that Table VI is enumerated is to use the preceding method preparation, but conspicuous modification is arranged.
Table VI
The representational 2-aminoalkyl-quinazoline that is substituted-4-ylamine analogues
Figure A0380245202181
Figure A0380245202211
Figure A0380245202221
Figure A0380245202251
Figure A0380245202311
Figure A0380245202391
Figure A0380245202421
Figure A0380245202471
Figure A0380245202481
Figure A0380245202501
Figure A0380245202511
Figure A0380245202531
Figure A0380245202551
Figure A0380245202571
Figure A0380245202591
Figure A0380245202601
Figure A0380245202611
Figure A0380245202621
Figure A0380245202631
Figure A0380245202661
Figure A0380245202681
Figure A0380245202701
Figure A0380245202741
Figure A0380245202751
Figure A0380245202761
Embodiment 3
The preparation of representative compounds
Present embodiment illustrates the preparation of the representational 2-hydroxy alkyl-quinazoline that is substituted-4-ylamine analogues.
A.[2-isopropoxy methyl-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-(4-fluoroform Base-phenyl)-amine ester (chemical compound 701)
1. 2-p-methylphenyl-3-5-flumethiazine
To 2-chloro-3-(trifluoromethyl)-pyridine (70.1 mM), p-methylphenyl dihydroxy boric acid (70.6 mM) and 2M sodium bicarbonate (175.0 mM) are at dimethyl ether (DME; 200 milliliters) in the mixture of degasification, under nitrogen atmosphere, add Pd (PPh 3) 4(2.8 mM).Mixture concentrates, with ethyl acetate extraction 80 ℃ of stirred overnight.With the sodium sulfate dehydration, vacuum concentration reaches by the silica gel liner and filters, and obtains 2-p-methylphenyl-3-5-flumethiazine.
2. 2-(4-methyl-3-nitro-phenyl)-3-(trifluoromethyl)-pyridine
Figure A0380245202772
To 2-p-methylphenyl-3-5-flumethiazine (8.4 mM) careful fuming nitric aicd (2 milliliters) that adds in the solution of sulphuric acid (6 milliliters).Mixture was stirring at room 60 minutes.Mixture to frozen water (30 milliliters), with ethyl acetate extraction, with the neutralization of 1N sodium hydroxide, with the sodium sulfate dehydration and at vacuum concentration, obtains 2-(4-methyl-3-nitro-phenyl)-3-(trifluoromethyl)-pyridine.
3. 2-nitro-4-(3-trifluoromethyl-pyridine-2-yl)-benzoic acid
In the solution of the mixture of pyridine (10 milliliters) and water (5 milliliters), be divided into several branches to 2-nitro-4-(3-trifluoromethyl-pyridine-2-yl)-benzoic acid (7.1 mM) and add KMnO 4(25.3 mM).Mixture stirred 4 hours at 110 ℃, added 25.3 mM KMnO with 10 ml waters again then 4Mixture is 110 ℃ of stirred overnight.Be cooled to room temperature, filter through C ore deposit liner.Filtrate is through vacuum concentration, with the water dilution, with the ethyl acetate solution washing.Aqueous solution is with the neutralization of 2N hydrochloric acid, and collecting precipitation, obtains 2-nitro-4-(3-trifluoromethyl-pyridine-2-yl)-benzoic acid.
4. 2-nitro-4-(3-trifluoromethyl-pyridine-2-yl)-benzyl amide
Figure A0380245202782
2-amino-4-(3-trifluoromethyl-pyridine-2-yl)-benzoic acid (25 gram) also concentrated with the mixture backflow of sulphinyl chlorine (50 milliliters) in 4 hours.Residue was dissolved in dichloromethane (DCM), and with ice-water bath cooling, ammonia is by solution 30 minutes, stirring at room 15 minutes.Concentrate to reach and obtain 2-nitro-4-(3-trifluoromethyl-pyridine-2-yl)-benzyl amide with water washing.
5. 2-amino-4-(3-trifluoromethyl-pyridine-2-yl)-benzyl amide
2-nitro-4-(3-trifluoromethyl-pyridine-2-yl)-benzyl amide (1.0 grams, 0.0032 mole) uses 50psi hydrogen and 100 milligram of 10% Pd/C in ethanol hydrogenation.After 16 hours, mixture filters through the C ore deposit, under reduced pressure concentrates, and obtains 2-amino-4-(3-trifluoromethyl-pyridine-2-yl)-benzyl amide and is solid.
6. 2-chloromethyl-7-(3-trifluoromethyl-pyridine-2-yl)-3H-quinazoline-4-one
2-amino-4-(3-trifluoromethyl-pyridine-2-yl)-benzyl amide (100 milligrams, 0.356 mM) is at 2-chloro-1,1, and the solution of 1-trimethoxy-ethane (138 ℃ of bp) was 130 ℃ of heating 4 hours.Mixture under reduced pressure concentrates, and obtains 2-chloromethyl-7-(3-trifluoromethyl-pyridine-2-yl)-3H-quinazoline-4-one and is oil, oil crystallization when placing.
7. 4-chloro-2-chloromethyl-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline
Figure A0380245202792
2-chloromethyl-7-(3-trifluoromethyl-pyridine-2-yl)-3H-quinazoline-4-one (deriving from previous reaction) and POCl 3Mixture refluxed 16 hours.Mixture is through cooling and under reduced pressure concentrated.The residue branch is dissolved in ethyl acetate and saturated sodium bicarbonate solution.The ethyl acetate part is again with the sodium bicarbonate washing, and dehydration (sodium sulfate) reaches under reduced pressure and concentrates then.Brown solid is filtered and is under reduced pressure concentrated through 2 inches silica gel (1: 1 ethyl acetate/hexane class eluant) and obtains 4-chloro-2-chloromethyl-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline.
8.[2-chloromethyl-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine
Figure A0380245202793
4-chloro-2-chloromethyl-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline (42 milligrams, 0.117 mM) and 4-trifluoromethyl-aniline (19 milligrams, 0.117 mM) heated 4 hours at 75 ℃ at the mixture of isopropyl alcohol (1 milliliter).Mixture, obtains [2-chloromethyl-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine and is a hydrochlorate then with the ether washing through cooling off and precipitate with washed with isopropyl alcohol.
9.[2-isopropoxy methyl-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine
To [2-chloromethyl-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine hydrochlorate (1.9 grams, 0.0037 mole) in the suspension of anhydrous isopropyl alcohol (100 milliliters), add 20 normal NaO-i-Pr (by sodium and isopropyl alcohol preparation).The lark mixture stirred 5 hours at 60 ℃, and cooling and vapourisation under reduced pressure are removed solvent.The residue branch is dissolved in ethyl acetate and water, and organic layer is with water washing (1 time).Organic layer is through dehydration (sodium sulfate) and concentrate acquisition [2-isopropoxy methyl-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine, is foams.
B.2-[4-(4-trifluoromethyl-phenyl amino)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-2- Base]-ethanol (chemical compound 702)
1. 3-benzyloxy propanoic acid
Sodium hydride (2.22 grams, 60% dispersion liquid at mineral oil, 55.4 mMs) is divided into aliquot and is added into benzylalcohol (4.0 grams, 37 mMs) cold (0 ℃) solution at toluene (100 milliliters).Dropwise add 3-ethyl bromide (8.0 gram, 44 mMs) to mixture, allow gained solution be warmed to room temperature and stirred 1 hour.Reaction is by adding the water quenching till whole foamings stop.Mixture is with ethyl acetate (100 milliliters) dilution and with water (100 milliliters) and saline solution (100 milliliters) extraction.Organic extract is with the sodium sulfate dehydration and under reduced pressure remove solvent, obtains the crude product ester and is clarified oil.Oil is dissolved in methanol (20 milliliters) and 6N sodium hydroxide (20 milliliters), stirs 1 hour, and enriched mixture (about 20 milliliters) reaches and dilutes with water (20 milliliters).Aqueous mixture with dichloromethane (40 milliliters) extraction once.Water is with the concentrated hydrochloric acid acidify, and with ethyl acetate (3 * 50 milliliters) extraction, the combination acetic acid ethyl ester extract dewaters with sodium sulfate.Under reduced pressure remove solvent, obtain title compound and be clarified oil (2.28 grams, 34.0%), it solidifies when placing.
2. 2-(2-benzyloxy-ethyl)-7-(3-trifluoromethyl-pyridine-2-yl)-3H-quinazoline-4-one
Figure A0380245202811
3-benzyloxy propanoic acid (1.66 grams, 9.19 mMs) is cooled to 0 ℃ at the solution of hexane class (40 milliliters), dropwise adds oxalyl chloride (3.50 grams, 27.6 mMs).After interpolation is finished, add DMF (2), the gained mixture stirred 1 hour.Under reduced pressure remove solvent, the crude product acyl chlorides is dissolved in anhydrous THF (20 milliliters).In the flask that separates, 2-amino-4-(3-trifluoromethyl-pyridine-2-yl)-benzyl amide (2.35 grams, 8.37 mMs) is dissolved in anhydrous THF (40 milliliters) and pyridine (0.727 gram, 9.19 mMs), be cooled to 0 ℃.The solution that contains the crude product acyl chlorides dropwise is added into second solution.Allow mixture be warmed to room temperature and stirred 1 hour.10% sodium bicarbonate (aqueous) solution (20 milliliters) is added into mixture, solution stirring 1 hour.Mixture is through concentrating (about 20 milliliters), with water (20 milliliters) dilution and with the concentrated hydrochloric acid acidify.Gained solution is with ethyl acetate extraction (3 * 50 milliliters).The combination organic extract reaches with the saline solution washing and dewaters with sodium sulfate.Solvent is under reduced pressure removed, and obtains title compound, the solid that is white in color (3.24 grams, 82.9%).
3. 2-(2-benzyloxy-ethyl)-4-chloro-7-(3-trifluoromethyl-pyridine radicals-2-yl)-quinoline azoles
2-(2-benzyloxy-ethyl)-7-(3-trifluoromethyl-pyridine-2-yl)-3H-quinazoline-4-one (3.24 grams, 7.26 mMs) is dissolved in chloroform (44 milliliters) and 2,6-lutidines (2.45 grams, 22.9 mMs).Dropwise add phosphoryl chloride phosphorus oxychloride (1.77 milliliters, 19.0 mMs), gained solution reflux 18 hours.Solution is under reduced pressure removed solvent through cooling.Crude product residue branch is dissolved in ethyl acetate (200 milliliters) and saturated sodium bicarbonate (aqueous) (200 milliliters).Remove organic facies, water extracts with ethyl acetate (200 milliliters).Make up two kinds of organic extracts, reach with saline (200 milliliters) washing and dewater with sodium sulfate.Remove solvent, obtain title compound and be light brown solid (2.47 grams, 73.1%).
(4.[2-2-benzyloxy-ethyl)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine
2-(2-benzyloxy-ethyl)-4-chloro-7-(3-trifluoromethyl-pyridine radicals-2-yl)-quinazoline (2.47 grams, 5.57 mMs) is dissolved in the solution of acetonitrile (50 milliliters) and 4-trifluoromethyl-aniline (0.986 gram, 6.12 mMs).Mixture heated to 80 ℃ 2 hours.Generate white precipitate.Solution cools off at ice bath, adds ether (25 milliliters).The evaporative removal white precipitate obtains title compound in the vacuum drying oven dehydration, is a hydrochlorate (2.96 grams, 87.8%).
5. 2-[4-(4-trifluoromethyl-phenyl amino)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-2-yl]-ethanol
Figure A0380245202822
[2-(2-benzyloxy-ethyl)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine hydrochlorate (2.96 grams, 4.89 mMs) is dissolved in methanol (150 milliliters) and adds 10% Pd/C (200 milligrams).Mixture at 60 ℃ 50p.s.i. hydrogenation 8 hours.Mixture filters by the C ore deposit fast, and C ore deposit filter cake washs with hot methanol (200 milliliters).Under reduced pressure remove solvent, obtain title compound one hydrochlorate, the solid that is white in color (1.75 grams, 69.5%).Mass spectrum 478.1.
C.[2-(2-methoxyl group-ethyl)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-(4-trifluoro Methyl-phenyl)-amine (chemical compound 703)
1,2-(2-methoxyl group-ethyl)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-phenol
In the solution of THF (20 milliliters), add 4-methoxyl group-butyl chloride (3.91 mM) to 2-amino-4-(3-trifluoromethyl-pyridine-2-yl)-benzyl amide (3.56 mM) and pyridine (3.91 mM).Mixture at room temperature stirred 20 minutes, added 20 milliliter of 20% sodium hydroxide, stirred 60 minutes down at 50 ℃.Concentrate, add water, filter and be acidified to pH=6, collecting precipitation obtains 2-(3-benzyloxy-propyl group)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-phenol.
2. 2-(2-methoxyl group-ethyl)-4-chloro-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline
Figure A0380245202832
Use the program of similar preamble explanation, prepare 2-(2-methoxyl group-ethyl)-4-chloro-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline by 2-(2-methoxyl group-ethyl)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-phenol.
(3.[2-2-methoxyl group-ethyl)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine
Use similar aforementioned program, by 2-(2-methoxyl group-ethyl)-4-chloro-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline preparation [2-(2-methoxyl group-ethyl)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine.Mass spectrum 492.1.
D.3-[4-(4-trifluoromethyl-phenyl amino)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-2- Base]-third-1-alcohol (chemical compound 704)
1. 2-(3-benzyloxy-propyl group)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-2-phenol
Figure A0380245202842
In the solution of THF (20 milliliters), add 4-methoxyl group-butyl chloride (3.91 mM) to 2-amino-4-(3-trifluoromethyl-pyridine-2-yl)-benzyl amide (3.56 mM) and pyridine (3.91 mM).Mixture at room temperature stirred 20 minutes, added 20 milliliter of 20% sodium hydroxide, stirred 60 minutes down at 50 ℃.Concentrate, add water, filter and be acidified to pH=6, collecting precipitation obtains 2-(3-benzyloxy-propyl group)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-phenol.
2. 2-(3-benzyloxy-propyl group)-4-chloro-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline
Use similar aforementioned program, prepare 2-(3-benzyloxy-propyl group)-4-chloro-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline by 2-(3-benzyloxy-propyl group)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-2-phenol.
3. 2-(3-benzyloxy-propyl group)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine
Figure A0380245202851
Use similar aforementioned program, prepare 2-(3-benzyloxy-propyl group)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl by 2-(3-benzyloxy-propyl group)-4-chloro-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline]-(4-trifluoromethyl-phenyl)-amine.
4. 3-[4-(4-trifluoromethyl-phenyl amino)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-2-yl]-third-1-alcohol
2-(3-benzyloxy-propyl group)-4-chloro-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline (0.5 mM) and 10% Pd-C are in the hydrogenation 30 hours under 50psi of the mixture of ethanol (100 milliliters).Filter, concentrate and chromatography, obtain 3-[4-(4-trifluoromethyl-phenyl amino)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-2-yl]-third-1-alcohol.Mass spectrum 492.1.
E.7-(3-trifluoromethyl-pyridine-2-yl)-2-methoxy-pyrido [3,2-d] pyrimidine-4-yl]-(4- Trifluoromethyl-phenyl)-amine (chemical compound 705)
1. 6 '-methoxyl group-3-trifluoromethyl-[2,3 '] bipyridyl
Figure A0380245202861
2-chloro-3-5-flumethiazine (37 grams, 0.2 mole), 2-methoxypyridine-5-dihydroxy boric acid (32 grams, 0.21 mole), tetrakis triphenylphosphine palladium (O) (9 grams, 7 mMs) and 2M potassium carbonate (150 milliliters) heated 8 hours at 90 ℃ under nitrogen atmosphere at the mixture of toluene (500 milliliters).Reactant mixture is through cooling and separate each layer.Water layer is with ethyl acetate (2 * 250 milliliters) extraction, and the combination organic layer is with 4M sodium hydroxide (250 milliliters), water (250 milliliters) and saline solution (250 milliliters) washing.Dehydration (magnesium sulfate) and under reduced pressure concentrated.Gained oil by flash chromatography art purification, obtains title compound (48.2 grams, 95%) at silica gel (50% ether/50% hexane), is water white oil.
2. 3-Trifluoromethyl-1 ' H-[2,3 '] bipyridyl-6 '-ketone
6 '-methoxyl group-3-trifluoromethyl-[2,3 '] bipyridyl (41 gram, 0.16 mole) was 30% hydrobromic acid/acetic acid (100 milliliters) reflux 1 hour.Mixture filters through cooling, and precipitation is washed with ether (100 milliliters).Precipitation moves to 10M sodium hydroxide (500 milliliters), stirs 1 hour.Solution is pH7 with salt acid elution to solution.Filter and collect white solid, air-dry, obtain title compound (36 grams, 93%), solid is white in color.
3. 5 '-nitro-3-Trifluoromethyl-1 ' H-[2,3 '] bipyridyl-6 '-ketone
Figure A0380245202863
To the 3-Trifluoromethyl-1 ' H-[2,3 '] bipyridyl-6 '-ketone (25 gram, 0.1 mole) in 0 ℃ solution, dropwise adds the solution of fuming nitric aicd (35 milliliters) and concentrated sulphuric acid (10 milliliters) at dense stream sour (100 milliliters).Reactant mixture be heated to 70 ℃ 1 hour, the cooling, to ice (500 milliliters) on.Mixture after filtration, filtrate with the 10M naoh treatment to the pH of solution be 4-5.Filter collecting precipitation, air-dry, obtain title compound (26.2 grams, 92%), solid is white in color.
4. 6 '-chloro-5 '-nitro-3-trifluoromethyl-[2,3 '] bipyridyl
Figure A0380245202871
5 '-nitro-3-Trifluoromethyl-1 ' H-[2,3 '] bipyridyl-6 '-ketone (25 grams, 0.088 mole), the solution of sulphinyl chlorine (300 milliliters) and DMF (3 milliliters) is heated to and refluxed 4 hours.Remove volatile matter by rotary evaporation, the residue branch is dissolved in ethyl acetate (350 milliliters) and saturated sodium bicarbonate solution (250 milliliters).Water layer is again with ethyl acetate (250 milliliters) extraction, and the combination organic layer washs with saline solution (250 milliliters).Dehydration (magnesium sulfate) and under reduced pressure concentrated obtains title compound (25 grams, 93%), is yellow oil.
5. 6 '-chloro-3-trifluoromethyl-[2,3 '] bipyridyl-5 '-Ji amine
Figure A0380245202872
In the solution of ethanol (300 milliliters) and water (50 milliliters), add iron powder (45 grams, 0.82 mole) to 6 '-chloro-5 '-nitro-3-trifluoromethyl-[2,3 '] bipyridyl (25 grams, 0.082 mole) and calcium chloride (11 grams, 0.1 mole).Solution reflux 1.5 hours, cooling and filter through the C ore deposit.Mixture under reduced pressure concentrates, and is dissolved in ethyl acetate (300 milliliters) once again and washs with saline solution (200 milliliters).Solution under reduced pressure concentrates, and by tomography purification rapidly, obtains title compound (19 grams, 85%) at silica gel (50% ether/50% hexane), is the lark solid.
6. 3-amino-5-[3-(trifluoromethyl) (2-pyridine radicals)] pyridine-2-carboxylic acid amides
6 '-chloro-3-trifluoromethyl-[2,3 '] bipyridyl-5 '-Ji amine (25 grams, 0.091 mole), zinc cyanide (6.75 grams, 0.058 mole), three [dibenzalacetones], two-palladium (pd 2(dba) 32.63 gram, 2.86 mMs) and 1,1 '-two (diphenylphosphino) halotrichite (DPPF; 3.16 gram, 5.72 mMs) the solution of DMF (250 milliliters) and water (2.5 milliliters) under nitrogen atmosphere 120 ℃ of heating 1 hour.Add water (30 milliliters), solution is finished hydrolysis 120 ℃ of heating 4 hours again.Reaction is cooled to 0 ℃, adds saturated ammonium chloride solution (200 milliliters), water (200 milliliters) and dense ammonium hydroxide (50 milliliters).After 1 hour, yellow mercury oxide reaches with the washing of 1: 1 ether-hexanes mixtures (200 milliliters) with water (200 milliliters) after filtration 0 ℃ of stirring.Solid obtains (23 grams, 90%) title compound then through air-dry in the vacuum drying oven dehydration.
7. 2-(chloromethyl)-7-[3-(trifluoromethyl) (2-pyridine radicals)]-3-pyridinium hydroxide [3,2-d] pyrimidin-4-one also
Figure A0380245202882
3-amino-5-[3-(trifluoromethyl) (2-pyridine radicals)] pyridine-2-carboxylic acid amides (23 grams, 81.5 mMs) and 2-chloro-1,1, the solution of 1-trimethoxy-ethane (250 milliliters) was 130 ℃ of heating 1 hour.By the evaporative removal volatile matter, abrasive solid (50% ether/50% hexane) obtains title compound, is light brown solid (21 grams, 76%).
8. 4-chloro-2-chloromethyl-7-(3-chloro-pyridine-2-yl)-pyrido [3,2-d] pyrimidine
Figure A0380245202883
2-(chloromethyl)-7-[3-(trifluoromethyl) (2-pyridine radicals)]-3-pyridinium hydroxide [3,2-d] pyrimidin-4-one (2.49 gram, 7.31 mMs) also, phosphoryl chloride phosphorus oxychloride (10 milliliters), 2,6-lutidines (2.13 milliliters, 18.3 mMs) and toluene solution reflux 8 hours.Remove solvent, crude product residue branch is dissolved in ethyl acetate (150 milliliters) and water (150 milliliters).Remove organic facies, water extracts with ethyl acetate (150 milliliters).The combination organic extract is with saturated sodium bicarbonate (aqueous) (150 milliliters) and saline solution (150 milliliters) washing, with sodium sulfate water.Remove solvent and obtain title compound, be light brown solid (230 grams, 87.6%).
(9.[2-2-chloromethyl)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine
4-chloro-2-chloromethyl-7-(3-chloro-pyridine-2-yl)-pyrido [3,2-d] pyrimidine (2.30 grams, 6.40 mMs) is dissolved in acetonitrile (20 milliliters) and 4-5-trifluoromethylaniline (1.13 grams, 7.04 mMs).Mixture was 80 ℃ of heating 18 hours.Mixture is cooled to 0 ℃, dilutes with ether (20 milliliters).One hydrochlorate of title compound forms light brown precipitation (2.85 grams, 85.6%), and it dewaters at vacuum drying oven by filtering to remove to reach.
10. 7-(3-trifluoromethyl-pyridine-2-yl)-2-methoxy-pyrido [3.2-d] pyrimidine-4-yl]-(4-trifluoromethyl-phenyl)-amine
Figure A0380245202892
[2-(2-chloromethyl)-7-(3-trifluoromethyl-pyridine-2-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine uses the first sodium oxide as processing as described in the preceding embodiment 1.A-9.So obtain 7-(3-trifluoromethyl-pyridine-2-yl)-2-methoxy-pyrido [3.2-d] pyrimidine-4-yl]-(4-trifluoromethyl-phenyl)-amino, be solid.Mass spectrum 479.1.
F.7-(3-methyl-pyridine-2-yl)-2-methoxy-pyrido [3,2-d] pyrimidine-4-yl]-(4-trifluoro Methyl-phenyl)-amine (chemical compound 706)
1. 5-bromo-3-nitropyridine-2-formonitrile HCN
2-amino-5-bromo-nitropyridine (2.18 grams, 10 mMs), Cupricin. (1.33 grams, 15 mMs) and nitrous acid tributyl (2.0 milliliters, 15 mMs) heated 2 hours at 60 ℃ at the solution of acetonitrile (50 milliliters).Solution divides to be dissolved in ethyl acetate (100 milliliters) and saturated aqueous sodium bicarbonate (100 milliliters) through cooling.Water layer is with ethyl acetate (2 * 50 milliliters) extraction, with water (100 milliliters) and saline solution (100 milliliters) washing, dehydration (magnesium sulfate) and evaporation.Solid by tomography purification rapidly, obtains title compound at silica gel (25% ether/75% hexane), is lark solid (934 milligrams, 41%).
2. 5-(3-methyl (2-pyridine radicals))-3-nitropyridine-2-formonitrile HCN
5-bromo-3-nitropyridine-2-formonitrile HCN (228 milligrams, 1.0 mMs), tetrakis triphenylphosphine palladium (O) (15 milligrams), 3-methyl-2-pyridine radicals zinc bromide (0.5M is at THF, 3 milliliters, 1.5 mMs) in the solution of THF (5 milliliters) 60 ℃ of heating 2 hours down.Cooling solution divides to be dissolved in ethyl acetate (10 milliliters) and saturated aqueous sodium bicarbonate (10 milliliters).Water layer is with ethyl acetate (2 * 15 milliliters) extraction, with water (10 milliliters) and saline solution (10 milliliters) washing, dehydration (magnesium sulfate) and evaporation.Obtain title compound, be lark solid (211 milligrams, 88%).
3. 3-amino-5-(3-methyl (2-pyridine radicals)) pyridine-2-carboxylic acid amides
Figure A0380245202911
5-(3-methyl (2-pyridine radicals))-3-nitropyridine-2-formonitrile HCN (1 gram, 4.1 mMs), ferrum (2.3 grams, 40 mMs) and calcium chloride (560 milligrams, 5 mMs) were the solution reflux of ethanol (15 milliliters) and water (4 milliliters) 1 hour.Mixture filters through the C ore deposit through cooling, washs with ethyl acetate.Filtrate is through evaporation, and residue is dissolved in ethyl acetate again.With water and saline solution washing, dehydration (magnesium sulfate) and evaporation obtain title compound, are lark solid (880 milligrams, 94%).
4. 7-(3-methyl-pyridine-2-yl)-2-methoxy-pyrido [3,2-d] pyrimidine-4-yl]-(4-trifluoromethyl-phenyl)-amine
Figure A0380245202912
Title compound is to use the described program of similar embodiment A, B, D, E, G and H, by 5 '-amino-3-methyl-[2,3 '] bipyridyl-6 '-carboxylic acid amide.
G.7-(3-trifluoromethyl-pyridine-2-yl)-2-methoxy-pyrido [3,2-d] pyrimidine-4- Base]-(4-trifluoromethyl-phenyl)-amine (chemical compound 707)
1. 7-(3-trifluoromethyl-pyridine-2-yl)-2-methoxy-3H-pyrido [3,2-d] pyrimidin-4-one
Figure A0380245202913
3-amino-5-[3-(chloro-pyridine-2-yl)] pyridine-2-carboxylic acid amides (340 milligrams, 1.21 mMs) uses methoxyl group-chloroacetic chloride (0.11 milliliter, 144 milligrams, 1.33 mMs) to handle in the solution of THF (5 milliliters) and pyridine (0.11 milliliter).Mixture at room temperature stirred 3 hours.Add 5N sodium hydroxide (10 milliliters) then, solution stirred again 18 hours.Solution uses the concentrated hydrochloric acid acidify through concentrating (about 5 milliliters).Aqueous mixture extracts with ethyl acetate (3 * 25 milliliters).The combination organic extract dewaters with sodium sulfate.Under reduced pressure remove solvent, obtain the title compound solid that is white in color.
2. 4-chloro-7-(3-trifluoromethyl-pyridine-2-yl)-2-methoxy-pyrido [3,2-d] pyrimidine
Figure A0380245202921
7-(3-trifluoromethyl-pyridine-2-yl)-2-methoxy-3H-pyrido [3,2-d] pyrimidin-4-one (276 milligrams, 0.822 mM) is dissolved in chloroform (25 milliliters) and 2,6-lutidines (294 milligrams, 2.74 mMs).Dropwise add phosphoryl chloride phosphorus oxychloride (0.255 milliliter, 2.74 mMs), gained solution reflux 24 hours.Solution is under reduced pressure removed solvent through cooling.Crude product residue branch is dissolved in ethyl acetate (50 milliliters) and saturated sodium bicarbonate (aqueous)(50 milliliters).Remove organic facies, water extracts with ethyl acetate (50 milliliters) again.Make up two kinds of organic extracts,, and dewater with sodium sulfate with saline solution (100 milliliters) washing.Remove solvent and obtain title compound, be light brown solid.
3. 7-(3-trifluoromethyl-pyridine-2-yl)-2-methoxy-pyrido [3,2-d] pyrimidine-4-yl]-(4-trifluoromethyl-phenyl)-amine
4-chloro-7-(3-trifluoromethyl-pyridine-2-yl)-2-methoxy-pyrido [3,2-d] pyrimidine (30 milligrams, 0.0934 mM) is dissolved in the solution of acetonitrile (3 milliliters) and 4-trifluoromethyl-aniline (18.0 milligrams, 0.112 mM).Mixture heated to 80 ℃ 16 hours.Reactant mixture cools off in ice bath, and adds ether (3 milliliters) filtration removal pale precipitation, dewaters in vacuum drying oven, obtains title compound, is a hydrochlorate.Mass spectrum 479.1.
H.7-(3-chloro-pyridine-2-yl)-2-methoxy-pyrido [3,2-d] pyrimidine-4-yl]-(4-trifluoro Methyl-phenyl)-amine (chemical compound 708)
1. 2-acetyl group-3-chloropyridine
Figure A0380245202931
3-chloro-2-cyanopyridine (10.0 grams, 0.072 mole, chemical pharmacy communique (1985) 33:565-571) is dissolved in anhydrous THF (200 milliliters) under nitrogen atmosphere, cool off at ice bath.Dropwise be added on 3.0M methyl magnesium iodide in the ether (48 milliliters, 0.14 mole) to reactant mixture, in ice bath, stirred 2 hours.To ice cold water, mixture is acidified to pH2 to 3 with 2.0N aqueous hydrochloric acid to reactant mixture.Reactant mixture dewaters with anhydrous magnesium sulfate with ethyl acetate (3 * 100 milliliters) extraction.Filter, vacuum concentration filters through the silica gel liner then, uses 20% ethyl acetate/hexane to make eluant.Under reduced pressure remove solvent, obtain pure 2-acetyl group-3-chloropyridine, be oil.
2. 1-(3-chloro-pyridine-2-yl)-3-dimethylamino propenone
2-acetyl group-3-chloropyridine (0.77 gram, 5.0 mMs) and N, dinethylformamide dimethylacetal (3.0 gram) was 105 ℃ of heating 20 hours.Under reduced pressure concentrate, obtain 1-(3-chloro-pyridine-2-yl)-3-dimethylamino propenone, be oil.
3. 2-amino-4-(3-chloro-pyridine-2-yl)-benzonitrile
Figure A0380245202941
1-(3-chloro-pyridine-2-yl)-3-dimethylamino propenone (1.05 grams, 5 mMs), 3-amino-3-methoxyl group-acrylonitrile hydrochlorate (1.35 gram, 10 mMs) and ammonium acetate (2.2 grams, 15.0 mMs) were the solution reflux of ethanol (25 milliliters) 20 hours.Mixture is through cooling, and under reduced pressure concentrating becomes dark oil.Residue is dissolved in ethyl acetate/water (100 milliliters).Aqueous solution is with ethyl acetate extraction, and ethyl acetate is washed with saline solution, and dehydration (magnesium sulfate) and vacuum concentration obtain 2-amino-4-(3-chloro-pyridine-2-yl)-benzonitrile, are brown solid.
4. 6-amino-3 '-chloro-[2,2 ']-bipyridyl-5-carboxylic acid amide
Concentrated sulphuric acid (10 milliliters) cools off under nitrogen atmosphere in ice bath.Be divided into several parts with 15 fens clock times and add 2-amino-4-(3-chloro-pyridine-2-yl)-benzonitrile (1.0 grams, 4.3 mMs).Stirred overnight at room temperature.Reactant mixture uses 10N aqueous sodium hydroxide to adjust pH to 10 on ice, filters out solid, and solid obtains 6-amino-3 '-chloro-[2,2 ']-bipyridyl-5-carboxylic acid amide with water washing and vacuum dehydration, is yellow solid.
5. 7-(3-chloro-pyridine-2-yl)-2-methoxy-3H-pyrido [2,3-d] pyrimidin-4-one
Figure A0380245202943
6-amino-3 '-chloro-[2,2 ']-bipyridyl-5-carboxylic acid amide (0.5 gram, 2.02 mMs) is dissolved in anhydrous THF (10 milliliters) under nitrogen atmosphere.Dropwise add the reactant mixture of pyridine (0.36 gram, 4.04 mMs) and methoxyacetyl chloride (0.48 gram, 4.04 mMs), at room temperature stirred overnight.Add 10% aqueous sodium bicarbonate (10 milliliters) and refluxed 4 hours.Vacuum concentration uses acetic acid to adjust pH to 6.0, and by solid collected by filtration, vacuum dehydration obtains 7-(3-chloro-pyridine-2-yl)-2-methoxy-3H-pyrido [2,3-d] pyrimidin-4-one, and solid is white in color.
6. 4-chloro-7-(3-chloro-pyridine-2-yl)-2-methoxy-pyrido [2,3-d] pyrimidine
7-(3-chloro-pyridine-2-yl)-2-methoxy-3H-pyrido [2,3-d] pyrimidin-4-one (0.25 gram), 2, the mixture that 6-lutidines (0.44 gram) reaches phosphoryl chloride phosphorus oxychloride in chloroform (5 milliliters) (0.51 gram) refluxed 20 hours.Mixture is through cooling and under reduced pressure concentrated.The residue branch is dissolved in ethyl acetate and saturated sodium bicarbonate solution.The ethyl acetate part under reduced pressure concentrates with extra sodium bicarbonate washing dehydration (sodium sulfate) then.The brown residue filters through 2 inches silica gel (1: 1 ethyl acetate/hexane class eluant), and under reduced pressure concentrates, and obtains 4-chloro-7-(3-chloro-pyridine-2-yl)-2-methoxy-pyrido [2,3-d] pyrimidine.
7. 7-(3-chloro-pyridine-2-yl)-2-methoxy-pyrido [3,2-d] pyrimidine-4-yl]-(4-trifluoromethyl-phenyl)-amine
Figure A0380245202952
4-chloro-7-(3-chloro-pyridine-2-yl)-2-methoxy-pyrido [2,3-d] pyrimidine (0.1 mM) and 4-trifluoromethyl-aniline (16.1 milligrams, 0.1 mM) heated 24 hours down at 80 ℃ at the mixture of acetonitrile (1 milliliter).Mixture is through cooling, and precipitation obtains 7-(3-chloro-pyridine-2-yl)-2-methoxy-pyrido [3,2-d] pyrimidine-4-yl with the ether washing]-(4-trifluoromethyl-phenyl)-amine, be a hydrochlorate.Mass spectrum 445.1.
I.[2-methoxy-7-(3-picoline-2-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)- Amine (chemical compound 709)
1. 7-bromo-2-(methoxy quinazoline-4-yl)-(4-trifluoromethyl-phenyl)-amine
Figure A0380245202961
7-bromo-2-(chloromethyl quinazoline-4-yl)-(4-trifluoromethyl-phenyl)-amine (derive from Embodiment C, 200 milligrams, 0.48 mM), 4.4M first sodium oxide was the mixture heated to 60 of methanol (2.4 milliliters) and methanol (1 milliliter) ℃ 4 hours.Be cooled to room temperature, the evaporative removal mixture.With ethyl acetate (10 milliliters) dilution, wash twice with water (each 10 milliliters).Organic layer (sodium sulfate) is through dehydration and evaporation.(3: 1 hexane classes: ethyl acetate) purification, acquisition 2-methoxy-7-(pyridin-4-yl-quinazoline-4-yl)-(4-trifluoromethyl)-amine (225 milligrams) is yellow solid by preparation property TLC.
2.[2-methoxy-7-(3-picoline-2-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine
(100 milligrams of 2-methoxy-7-(pyridin-4-yl-quinazoline-4-yl)-(4-trifluoromethyl)-amine, 0.243 mM), 3-methyl-2-pyridine radicals zinc bromide (1 milliliter of 0.5M THF solution), 1, the mixture of tetrakis triphenylphosphine palladium (O) (50 milligrams, 0.043 mM) heated 3 hours under nitrogen at 80 ℃ in the 2-dimethoxymethane (5 milliliters).Be cooled to room temperature and diluting with ethyl acetate (10 milliliters).With water (2 * 10 milliliters) washing, organic layer is through dehydration (sodium sulfate) and evaporation.Obtain [2-methoxy-7-(3-picoline-2-yl)-quinazoline-4-yl]-(4-trifluoromethyl-phenyl)-amine (38 milligrams) by preparation property TLC purification, be pale solid.
J. other representational 2-hydroxy alkyl-quinazoline that is substituted-4-ylamine analogues
The chemical compound that Table VII is enumerated is to use the preceding method preparation, but conspicuous modification is arranged.
Table VII
The representational 2-hydroxy alkyl-quinazoline that is substituted-4-ylamine analogues
Figure A0380245202981
Figure A0380245203021
Figure A0380245203091
Figure A0380245203101
Figure A0380245203121
Figure A0380245203131
Figure A0380245203151
Figure A0380245203161
Figure A0380245203171
Figure A0380245203181
Figure A0380245203201
Figure A0380245203211
Figure A0380245203231
Figure A0380245203251
Figure A0380245203261
Figure A0380245203271
Figure A0380245203281
Embodiment 4
Shift cell and the film preparation that infects through VR1
Present embodiment explanation is shifted the film that the cell that infects and preparation contain VR1 through VR1 and is analyzed (embodiment 5) to be used for capsaicin in conjunction with calibrating.
Encode human capsaicin receptor (United States Patent (USP) the 6th, 482, No. 611 SEQ ID NO:1, the 2 or 3) time cloning of whole length of cDNA is used for the reorganization performance of cells of mamma animals in plastid pBK-CMV (history tap genes (Stratagene), California La Hela).
People embryo's kidney (HEK293) cell uses standard method to infect with the pBK-CMV performance constituting body transfer of the human capsaicin receptor of the whole length of encoding.Shift metainfective cell and in the culture medium that contains G418 (400 mcg/ml), selected for two weeks, obtain to compile thing through the stable infection cell that shifts.Compile thing thus and isolate independent pure strain, obtain the stable cell of clone and test subsequently being used for by restriction dilution.
Be used for the radioactivity ligand in conjunction with test, cell inoculation grows to about 90% and merges in the T175 Tissue Culture Flask that does not contain the antibiotic culture medium.Tissue Culture Flask washs with PBS then, is containing the PBS results of 5mM EDTA.Cell is stored to calibrating at-80 ℃ and is analyzed by gentle centrifugal granulating.
Before through refrigerated cell by means of organizing homogenizer to destroy homogenize buffer (5mM KCl 5,5.8mM NaCl, 0.75mM CaCl in ice-cold HEPES 2, 2mM MgCl 2, 320mM sucrose and 10mM HEPES pH7.4).Cell homogenize thing removes nuclear part and chip at first centrifugal 10 minutes of 1000xg (4 ℃), derives from then that centrifugal clear liquid is further 35 for the first time, and 000xg (4 ℃) obtained partially purified membrane portions in centrifugal 30 minutes.Before calibrating was analyzed, film was suspended in HEPES homogenize buffer once again.Whole part of film homogenize thing visitd the California He Kelisi of Thunder God department with cause Bradford method (visiing thunder (BIO-RAD)) protein calibrating analysis kit group #500-0001) the mensuration protein concentration.
Embodiment 5
The calibrating of capsaicin receptors bind is analyzed
The present embodiment explanation can be used for measuring chemical compound the combination calibrating of the representative capsaicin receptor of the binding affinity of capsaicin (VR1) receptor is analyzed.
With [ 3H] the bonded calibrating of RTX (RTX) is analyzed is to carry out as described in Szallasi and Blumberg (1992) pharmacological testing treatment periodical 262:883-888 haply.In this scheme, after association reaction finishes, by adding cattle α 1Acid glycoprotein (100 microgram/pipe) reduces non-specific RTX combination.
[ 3H] RTX (37 occupy gift/mM) is by chemosynthesis and assay laboratory, National Cancer Institute-Fei Delieke cancer research centre of development, Maryland State Fei Delieke synthetic with obtain.[ 3H] RTX derives from commercial suppliers (for example skill company, a New Jersey Zi Kawei are given birth in method horse West Asia, Ah not mountain (Amersham) (Pharmacia)).
The film homogenize thing of embodiment 4 such as preceding centrifugal, resuspending to 333 mcg/ml protein concentration in the homogenize buffer.Place on ice in conjunction with the calibrating analysis of mixtures, contain [ 3H] RTX (specific activity 2200 millicuries gift/milliliter), 2 microlitre cold test chemical compounds, 0.25 mg/ml bovine serum albumin (Ke En (Cohn) part of V) and 5 * 10 4-1 * 10 5Shift infection cell through CR1.Final volume uses aforementioned ice-cold HEPES homogenize buffer (pH7.4) to be adjusted to 500 microlitres (being used for competition analyzes in conjunction with calibrating) or 1000 microlitres (being used for saturated combination calibrating analyzes).Non-specific binding is defined as in 1 μ M on-radiation RTX (Ai Lixisi (Alexis) company; Santiago, California) there is the combination that occurs down.In order to reach saturated combination, use 1 to 2 dilution with the concentration range of 7-1000pM add [ 3H] RTX.Typically, every saturated binding curve is collected 11 concentration point.
It is at 60pM[that competition is analyzed in conjunction with calibrating 3H] RTX exist down and not the isoconcentration test compound carry out under existing.Association reaction is to transfer into 37 ℃ of water-baths and begin by examining and determine analysis of mixtures, and is being finished in cooled on ice by test tube behind the culture period through 60 minutes.With membrane-bound RTX is to separate with free RTX, and with any α 1The bonded RTX of acid glycoprotein separates, separate mode is that Wa Leke (WALLAC) the glass fibre filter membrane (rich golden Emma (PERKIN-ELMER) company, Maryland State capping plug fort) that soaked 2 hours with 1.0% PEI (the poly-ethyl imines of stretching) in advance before use filters.Make the filter membrane drying overnight, add Wa Leke BETA SCINT flicker fluid then and in Wa Leke 1205BETA plate, count.
By means of computer program FIT P (biosoftware (Biosoft) company, Montana State model Age-old pine trees), as described in people such as Szallasi (1993) pharmacological evaluation treatment periodical 266:678-683, allosteric Xi Er (Hill) equation conjunction measuring pH-value determination pH is gone out the balance incorporating parametric.Chemical compound provided herein has capsaicin receptor K usually iValue is less than 4 μ M, in this calibrating is analyzed preferably less than 1 μ M, 100nM, 50nM, 25nM, 10nM or 1nM.
Embodiment 6
The calibrating of calcium mobility is analyzed
Present embodiment illustrates representative calcium mobility calibrating and analyzes, be used to monitor and express of the reaction of capsaicin recipient cell the class vanilloid ligand seat of capsaicin and other capsaicin receptor, and the agonist activity and the antagonist activities of rating test chemical compound.
Cell is expressed plastid (as described in embodiment 4) and is shifted infection, express human capsaicin receptor thus, this cell is taking the black wall clear bottom 96 hole orifice plate (#3904 of health (FALCON), New Jersey, Bake honest Dixon (BECTON-DICKINSON), Franklin lake) inoculating and grow to 70%-90% on merges.Culture medium is by emptying in the 96 hole orifice plates, add FLUO-3 AM calcium sensitive dye (molecular probe company, the E Legang state is Jin Shi still) [the dye solution: 1 milligram of FLUO-3 AM to each hole, 440 microlitre DMSO and 440 microlitres, 20% general imperial nicotinic acid (pluronic acid) are at DMSO, at Cray Bai Linge (Krebs-Ringer) HEPES (KRH) buffer (25mMHEPES, 5mM KCl, 0.96mM NaH 2PO 4, 1mM MgSO 2, 2mM CaCl 2, the 5mM glucose, 1mM benemid (probenecid), pH7.4) dilution is 1: 250, every hole 50 microlitre weak solutions].Plate is covered by aluminium foil, cultivates 1-2 hour down at 37 ℃ in the environment that contains 5% carbon dioxide.After the cultivation, by orifice plate emptying dyestuff, cell is washed once with the KRH buffer, and resuspending is in the KRH buffer.
Agonist (Europe method Neil (olvanil) for example, capsaicin or RTX) calcium that brings out moves and is to use FLUOROSKAN ASCENT (experimental system company Massachusetts Franklin) or FLIPR (fluorescence imaging orifice plate reader system, molecular device, California Sani Wei Er) the instrument supervision.Not isocyatic antagonist ammoniated ruthenium oxychloride or capsaicin receptor blocker (RBI; Massachusetts Na Tike) is added into cell jointly with agonist (for example 25-50nM capsaicin).Calcium reaction to agonist brings out is used for producing IC in back 30 seconds to 60 seconds gained data of using of agonist 50Value.KALEIDAGRAPH software (collaboration software company, the auspicious fourth in Binzhou) is used for data substitution equation:
y＝a*(1/(1+(b/x) C))
The IC of assaying reaction 50In this equation, y is the maximum fluorescence signal, and x is agonist or antagonist concentration, and a is E Max, the b correspondence is at IC 50Value, and c is a hill coefficient.
Express of the reaction of capsaicin recipient cell in order to measure test compound antagonism (inhibition), at first measure capsaicin IC capsaicin or other class Rhizoma et radix valerianae agonist 50Add 20 microlitre KRH buffer and 1 microlitre DMSO again to each cell hole, each cell hole is to prepare as described above.100 microlitre capsaicins are automatically transferred to each hole by the FLIPR instrument in the KRH buffer.Use 8 concentration-response curves to measure capsaicin IC 50, final capsaicin concentration is 1nM to 3 μ M.
Test compound is dissolved in DMSO, dilutes in 20 microlitre KRH buffer, and the test compound final concentration is 1 μ M to 5 μ M in the hole is analyzed in calibrating, is added into the cell of preparation as described above.Containing the cell for preparing and 96 hole orifice plates of test compound in the dark at room temperature cultivated 0.5 hour to 6 hours.Importantly cultivating can not be continuously above 6 hour.Just in time before measuring fluorescence reaction, 100 microlitre capsaicins have by the concentration-response curve in the KRH buffer and record IC 50The concentration twice is added into each holes of 96 hole orifice plates automatically by the FLIPR instrument, and obtaining the final sample volume is 200 microlitres, and whole capsaicin concentration equals EC 50The test compound final concentration is 1 μ M to 5 μ M in the calibrating analysis hole.Be exposed to capsaicin IC 50Typical cells have about 10, the 000 relative fluorescence units of fluorescence reaction.With the matched group of coupling relatively, the capsaicin receptor antagonist can reduce this reaction at least about 20%, preferably at least about 50%, and most preferably at least 80%.The IC that the required antagonist concentration that 50% reduction is provided is antagonist 50, preferably be lower than 1 μ M, 100nM, 10nM or 1nM.
Chemical compound is via in the presence of no capsaicin, RTX or other known capsaicin receptor agonists as the ability of capsaicin receptor agonists, uses preceding method, measures the fluorescence reaction of the cell of expressing the capsaicin receptor and measures.Causing cell to have to be higher than the chemical compound of the fluorescence of background is the capsaicin receptor agonists.Some preferred The compounds of this invention are antagonist, antagonist does not contain the agonist activity haply, and as be lower than 4nM at compound concentration in this kind calibrating is analyzed, more preferably concentration is lower than 10 μ M, and most preferable concentrations is when being less than or equal to 100 μ M, do not have that detectable agonist is active to be confirmed.
Embodiment 7
The microsome test tube test half-life
Present embodiment shows that using the representational liver microsomes half-life to examine and determine analyzes the elimination half life values (t that appraises through comparison chemical compound 1/2Value).
The people's hepatomicrosome that compiles is to derive from XenoTech LLC, No. 3800, Cambridge road, 66103 Kansas City, the Kansas State (model H0610).This kind hepatomicrosome also can derive from test tube technology company (Maryland State Ba Er Supreme Being rub) or organize technology transition (New Jersey Edison).Prepare 6 test reactions, each contains 25 microlitre microsomes, the test compound solution of 5 microlitres, 10 μ M, and phosphate buffer (19 milliliters of 0.1M NaH of 399 microlitre 0.1M 2PO 4, 81 milliliters of 0.1MNa 2HPO 4, use phosphoric acid to be adjusted to pH7.4).The 7th prepared in reaction contains 25 microlitre microsomes as positive controls, and 399 microlitre 0.1M phosphate buffers and 5 microlitres, 100 μ M have the compound solution (for example Dai Xipan (DIAZEPAM) but or Luo Zaiping (CLOZAPINE)) of known metabolisming property.Be reflected at 39 ℃ of pre-down cultivations 10 minutes.
The cofactor mixture is via 16.2 milligrams of NADP and 45.4 milligrams of glucose 6-phosphoric acid are diluted in 4 milliliters of 100mM magnesium chloride preparations.Glucose 6-phosphoric acid dehydrogenase solution is via with 214.3 microlitre glucose 6-phosphoric acid dehydrogenase suspension (lark Jia Manhan (Boehringer-Manheim) models 0737224, roche molecular biochemicals company distribution, Pori, At, seal ground, Indiana State) is diluted in the preparation of 1285.7 microlitre distilled water.71 microlitre initial action mixture (3 milliliters of cofactor mixture; 1.2 milliliter glucose 6-phosphoric acid dehydrogenase solution) be added into 5 in 6 test reactions, and be added into positive control.71 microlitre 100mM magnesium chlorides are added into the 6th test reaction, and the 6th test reaction is used as negative control.In each time point (0,1,3,5 and 10 minute), each 75 microlitre reactant mixture amount of dripping is gone into the hole of 96 hole depth orifice plates, and the hole contains the ice-cold acetonitrile of 75 microlitres.Sample counter-rotating is mixed, with centrifugal 10 minutes of 3500rpm (rope method (Sorval) T 6000D centrifuge, H1000B rotor).75 microlitres derive from the hole that each clear liquid that reacts is transferred to 96 hole orifice plates, and 150 microlitres, 0.5 μ M compound solution is contained in every hole, has known LCMS side and paints (internal standard).Each sample carries out lcms analysis, measures as AUC without metabolic test compound, and compound concentration was mapped with respect to the time, the t of test compound 1/2Value is measured through extrapolation.
Preferred The compounds of this invention has test tube test t at human liver's microsome 1/2Value less than 4 hours, and was preferably 30 minutes to 1 hour greater than 10 minutes.
Embodiment 8
The MDCK toxicological detection is analyzed
The present embodiment explanation uses Martin's card to analyze the toxicity of appraising through comparison chemical compound than the calibrating of (Madin Darby) dog kidney (MDCK) cell cellular toxicity.
1 microlitre test compound is added into each hole of clear bottom 96 hole orifice plates (Parker (PACKARD), Kang Naitige state Maryland), and it is 10 μ M, 100 μ M or 200 μ M that the chemical compound of acquisition is analyzed final concentration through calibrating.The solvent that does not contain test compound is added into control wells.
Mdck cell, ATCC numbering CCL-34 (U.S.'s kind type is cultivated and collected meeting, Virginia Ma Nasa) remains under the aseptic condition according to the indication of ATCC production information table.Merge mdck cell and be diluted to concentration 0.1 * 10 through trypsinization, results, use warm (37 ℃) culture medium (the minimum necessary culture medium Ying Shi of VITACELL, ATCC catalog numbering 30-2003) 6Cells/ml.The rare cell of 100 microlitres is added into each hole, but except five standard curve control wells, the standard curve control wells contains the warm culture medium of 100 microlitres but do not contain cell.Then orifice plate under 37 ℃ in 95% oxygen, 5% carbon dioxide with constant stir culture 2 hours.After the cultivation, every hole adds 50 microlitre cells of mamma animals decomposing solutions, Parker's closedtop paster on each port lid, orifice plate on suitable jolting device with about 700rpm jolting 2 minutes.
Cause toxic chemical compound and will reduce the output of ATP with respect to unprocessed cell.The luminous ATP of Parker (Kang Naitige state Maryland) ATP-LITE-M detects the external member group, and production code member 6016941 is used for measuring the output at the ATP of treated mdck cell and unprocessed mdck cell according to manufacturer's indication usually.Allow Parker ATP LITE-M reactant balance to room temperature.In case after the balance, the lyophozyme matrix solution is modulated again at 5.5 milliliters of enzyme substrate buffer (deriving from the external member group).Lyophilizing ATP standard solution is modulated again at deionized water and is obtained 10mM stand-by buffer liquid.As for 5 control wells, 10 microlitres are to be listed as each hole that the Parker's standard solution that dilutes is added into the standard curve control wells through one, come at each hole acquisition final concentration 200nM that continues, 100nM, 50nM, 25nM, reach 12.5nM.Parker's enzyme matrix solution (50 microlitre) is added into each hole, add a cover then, orifice plate at suitable jolting device about 700rpm jolting 2 minutes.White Parker's paster is labelled to each bottom, hole, and sample is wrapped in and is positioned over adjustment adaptation in 10 minutes dark place, dark place in the metal forming.Luminous in 22 ℃ of following use luminescent counters (for example the Parker pushes up counting microplate flicker and luminescent counter or carries and agree SPECTRAFLUOR PLUS) mensuration then, calculate ATP concentration by standard curve.The ATP concentration of the more unprocessed raji cell assay Raji of ATP concentration ratio of the cell of service test compound treatment.Use the cell of 10 μ M optimization test compound treatment to have ATP concentration and account for 80% of unprocessed cell at least, preferably at least 90%.When using 100 μ M test compound concentration, use the cell of optimization test compound treatment to have ATP concentration and account at least 50% of the ATP concentration that gets in unprocessed cell detection, and preferably at least 80%.
Embodiment 9
The calibrating of dorsal root ganglion cell is analyzed
The representative dorsal root ganglion cell calibrating of the VR1 antagonist activities of this example explanation comparation and assessment chemical compound is analyzed.
Downcut DRG by neonate rat, separate, use standard method to cultivate (Aguayo and White (1992) brain research 570:61-67).Cultivate after 48 hours, cell is washed once, with calcium sensitive dye Fluo 4 AM (2.5-10 microgram milliliter; Ferrum fluorine laboratory (TefLabs), Dezhou Austin) cultivated 30-60 minute.Cell is washed 1 time then, adds not the isoconcentration chemical compound to cell.Add capsaicin to cell, the result causes CR1 dependency cellular calcium concentration to increase, and is to use fluorescent agent to be detected by the Fluo-4 change in fluorescence.Data collection 60-180 time second is measured the maximum fluorescence signal.The fluorescence signal function construction that is compound concentration is discerned and is reached the activation of 50% capsaicin and suppress desired concn then, or IC 50The capsaicin receptor antagonist preferably has IC 50Be lower than 1 μ M, 100nM, 10nM or 1nM.
Embodiment 10
The zoopery pattern that pain relief is measured
This example explanation comparation and assessment are provided the exemplary process of pain relief degree by chemical compound.
A. pain relief test
Following method can be used to appraise through comparison the alleviation of pain.
The mechanicalness pain sensation is unusual
The mechanicalness pain sensation unusual (to the abnormal response of destructive stimulus) is as people such as Chaplan (1994) neuroscience method periodical 53:55-63 and Tal and Eliav (1998) pain 64 (3) haply: comparation and assessment as described in the 511-518.A series of have do not wait inflexible Feng Fulei (von Frey) filament (typical case has a series of 8-14 root filaments) to be applied to the back foot plate surface, applied pressure is enough crooked filament just.Filament is maintained at this position and is no more than 3 seconds, or is maintained until rat and shows till the reaction of positive paralgia.Positive paralgia reaction comprises lifts high this sole, then licks at once and licks or this sole of jolting.Use Dixon (Dixon) up and down method measure the order of administration and the frequency of administration of indivedual filaments.Test is that the central authorities with this series begin, and subsequently with consecutive order, rises continuously or descends continuously and use filament, according to the negative reaction of reaction or the positive reaction decision of initial filament gained.
If rat is used compound treatment, need to use the Feng Fulei filament with higher firm intensity to stimulate and just can bring out the positive paralgia reaction that more unprocessed rat or mediator are handled the rat matched group, then this chemical compound can effectively reverse or prevent mechanicalness pain sensation exception class like symptom.In addition or in addition, test chronic pain chemical compound can carry out before compound administration and after the administration.During this kind calibrating is analyzed, active compound can obtain, with handle before bring out reaction the filament hardness ratio or with also suffer from the chronic pain animal but unprocessed or use mediator to handle animal relatively, the filament hardness of bringing out reaction needed increases accepting to handle back hardness.Test compound is to give after pain begins preceding or begins.When test compound is when giving after pain begins, test is to carry out after administration 10 minutes to 3 hours.
Mechanical hyperalgesia
Mechanical hyperalgesia (reaction to pain stimulation is exaggerative) is as people such as Koch (1996) pain relieving 2 (3) haply: test as described in the 157-164.It is indoor that rat is placed on each of cage of warm perforated metal base plate.At the sole of the arbitrary rear foot of gentle acupuncture rat, measure rear foot retraction persistent period after the acupuncture (be animal keep sole upwards sole is put back the floor time before).
If the sole retraction time shortens by adding up to go up significantly, then animal produces the mechanical hyperalgesia minimizing.Test compound can give after pain begins preceding or begins.Pain is begun the back administered compound, and test is to carry out in 10 minutes to 3 hours after administration.
Hot perceptual hyperesthesia
Hot perceptual hyperesthesia (to the exaggerative reaction of harmful thermostimulation) is as people such as Hargreaves (1988) pain 32 (1) haply: mensuration as described in the 77-88.In brief animal rear foot sole persistence is applied constant radiant heat source.The rear foot retraction time (promptly executing the time of heat before animal is moved sole) also is defined as hot threshold value or hot incubation period, can measure the sensitivity of the animal rear foot to heat.
If the rear foot retraction time significantly shortens (instant heating increases or hot incubation period of increase the threshold value of reaction), then chemical compound produces the reduction of hot perceptual hyperesthesia.Test compound is to begin preceding or pain gives after beginning in pain.It is to carry out in 10 minutes to 3 hours after administration that pain begins back administered compound test.
B. pain pattern
Pain can use following any method to bring out, and allows the pain relieving effect of test compound.Usually chemical compound provided herein causes reducing in statistically evident pain, uses male SD rat and following at least a kind of pattern, is measured by aforementioned at least a method.
Acute inflammation pain pattern
Acute inflammation pain is to use the carrageenin pattern to bring out, haply as people such as Field (1997) Britain pharmacology periodical 121 (8): as described in the 1513-1522.100-200 microlitre 1%-2% carrageenin injection of solution is gone into the rat hind paw.The sensitivity of preceding method experimental animal to thermostimulation and mechanical stimulus used in injection back 3 to 4 hours.Test compound (0.01 to 50 mg/kg) is to give animal before test or before the carrageenin injection.Chemical compound can be oral or be given through any injecting pathway, or is locally applied to sole.Can obtain the significantly decline on statistics of the unusual and/or hot perceptual hyperesthesia of the mechanicalness pain sensation by lenitive chemical compound in this kind pattern.
Chronic inflammation pain pattern
Chronic inflammation pain is to use one of following scheme to bring out:
1. roughly as people such as Bertorelli (1999) Britain pharmacology periodical 128 (6): people such as 1252-1258 and Stein (1998) pharmacology biochemical behavior 31 (2): as described in the 455-51, the complete good fortune Lang Shi of 200 microlitres (Freund ' s) adjuvant (0.1 milligram of heat-killed and exsiccant in conjunction with bacillus) is injected into the rat hind paw: 100 microlitres inject instep surface and 100 microlitres inject foot plate surface.
2. roughly as people such as Abbadie (1994) neuroscience periodical 14 (10): as described in the 5865-5871, rat is injected 150 microlitre CFA (1.5 milligrams) in tibia-midtarsal joints.
Before any scheme injection CFA, each laboratory animal is obtained the indivedual datum line sensitivitys of animal hind paw to mechanical stimulus and thermostimulation.
Behind the injection CFA, rat is tested hot perceptual hyperesthesia as described above, the mechanicalness pain sensation reaches mechanical hyperalgesia unusually.In order to confirm the development of symptom, rat was tested in the 5th, 6 and 7 in CFA injection back.On 7th, animal service test chemical compound was that morphine or mediator are handled.1-5 mg/kg oral dose morphine is suitably used as positive controls.The typical case uses 0.01-50 mg/kg test compound dosage.Before test or before test once a day or every day secondary or three continuous a few days of every day give chemical compound with single heavy dose.Medicine be orally give or outside any intestinal approach give, or be locally applied to animal.
The result represents with maximum possible efficient percentage ratio (MPE).0%MPE is defined as the analgesic effect of mediator, and 100%MPE is defined as animal and returns CFA datum line sensitivity in early stage.But this pattern alleviating pain to chemical compound obtains MPE and is at least 30%.
Chronic neuropathic degeneration pain pattern
Chronic neuropathic degeneration pain is to use tightens injury (CCI) for a long time to rat sciatic nerve and brings out, haply as described in Bennett and Xie (1988) the pain 33:87-107.Rat is through anesthesia (for example use injected dose 50-65 mg/kg pentobarbital in the abdomen, but if required extra injection anesthesia is arranged).Each hind leg outside is through shaving hair and sterilization.Use aseptic technique, cut at middle buttocks height in the hind leg outside.The femur biceps directly excises, and exposes sciatic nerve.At the hind leg of animal, tie up four frenulums loosely around sciatic nerve, at interval about 1-2 millimeter.At the hind leg of opposite side, sciatic nerve not ligation is also unprocessed.Muscle seals with continuous mode, and skin uses wound clips or suture sealing.The mechanicalness pain sensation as preamble explanation comparation and assessment rat is unusual, mechanical hyperalgesia and hot perceptual hyperesthesia.
Can lenitive chemical compound in this pattern before near experiment with single heavy dose of administration or continuous a few days administration: before test once a day or secondary or three administration (0.01-50 mg/kg, oral, injection or topical) chemical compound cause that the mechanicalness pain sensation is unusual, mechanical hyperalgesia and/or hot perceptual hyperesthesia significantly reduce on statistics.

Claims (120)

1.一种如下式的化合物：1. A compound of the following formula: 或其医药上可接受的盐，其中：or a pharmaceutically acceptable salt thereof, wherein: V、X、W、Y及Z各自分别为N或CR1，其条件是V及X中的至少一个为N；V, X, W, Y and Z are each independently N or CR 1 with the proviso that at least one of V and X is N; U为N或CR2，但若V及X为N，则U为CR2；U is N or CR 2 , but if V and X are N, then U is CR 2 ; R1在各次出现时分别是选自氢、卤原子、羟基、氨基、C1-C8烷基、卤代C1-C8烷基、C1-C8烷氧基、卤代C1-C8烷氧基及一-(C1-C8烷基)氨基及二-(C1-C8烷基)氨基；R 1 is selected from hydrogen, halogen atom, hydroxyl, amino, C 1 -C 8 alkyl, halogenated C 1 -C 8 alkyl, C 1 -C 8 alkoxy, halogenated C 1 -C 8 alkoxy and mono-(C 1 -C 8 alkyl) amino and di-(C 1 -C 8 alkyl) amino; R2为：(i)氢、卤原子、氰基或-COOH；R 2 is: (i) hydrogen, halogen atom, cyano group or -COOH; (ii)C1-C8烷酰基、C2-C8烷酮或C1-C8氨基甲酸根，其各自为未经取代或被1至9个分别选自Rb的取代基取代；或(ii) C 1 -C 8 alkanoyl, C 2 -C 8 alkanone or C 1 -C 8 carbamate, each of which is unsubstituted or substituted by 1 to 9 substituents respectively selected from R b ; or (iii)如式-Rc-M-A-Ry的基团，其中：(iii) A group of formula -Rc - MARy , wherein: Rc为C0-C3烷基；R c is C 0 -C 3 alkyl; M为键连接、N(Rz)、O、S、SO2、C(＝O)pN(Rz)、N(Rz)C(＝O)p、M is bond linkage, N(R z ), O, S, SO 2 , C(=O) p N(R z ), N(R z )C(=O) p , SO2N(Rz)或N(Rz)SO2，其中p为0或1；SO 2 N(R z ) or N(R z )SO 2 , where p is 0 or 1; A为键连接或C1-C8烷基，任选地被1至3个分别选自Rb的取代基取代；以及A is bonded or C 1 -C 8 alkyl, optionally substituted by 1 to 3 substituents selected from R b respectively; and Ry及Rz若存在时则为：R y and R z, if present, are: (a)分别为氢、C1-C8烷基、C2-C8烯基、C2-C8炔基、C6-C10芳基C1-C8烷基、C2-C8烷基醚、C1-C8烷氧基、4元至10元碳环或杂环，或接合至Rc而形成一个4元至10元碳环或杂环，其中各个Ry及Rz分别为未经取代或被1至9个分别选自Rb的取代基取代；或(a) hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 6 -C 10 aryl, C 1 -C 8 alkyl, C 2 -C 8 alkyl ether, C 1 -C 8 alkoxy, 4 to 10 membered carbocyclic or heterocyclic ring, or joined to R c to form a 4 to 10 membered carbocyclic or heterocyclic ring, wherein each of R y and R z are each unsubstituted or substituted by 1 to 9 substituents respectively selected from R b ; or (b)接合而形成一个4元至10元碳环或杂环，其为未经取代或被1至9个分别选自Rb的取代基取代；(b) joined to form a 4- to 10-membered carbocyclic or heterocyclic ring, which is unsubstituted or substituted by 1 to 9 substituents selected from R respectively; Ar2为5元至7元芳香族杂环，任选地被1至3个分别选自式LRa的群组的取代基取代；Ar 2 is a 5-7 membered aromatic heterocycle, optionally substituted by 1 to 3 substituents selected from the group of formula LR a ; Ar1为5元至10元芳香族碳环或杂环，任选地被1至3个分别选自式LRa的群组的取代基取代；Ar is a 5- to 10-membered aromatic carbocyclic or heterocyclic ring, optionally substituted by 1 to 3 substituents selected from the group of formula LRa ; L在各自出现时分别是选自键连接、-O-、-C(＝O)-、-OC(＝O)-、-C(＝O)O-、-O-C(＝O)O-、-S(O)m-、-NRx-、-C(＝O)NHRx-、-NHRxC(＝O)-、-NRxS(O)m-、S(O)mNRx-及-N[S(O)mRx]S(O)m-；其中m在各自出现时分别是选自0、1及-2；以及Rx在各次出现时分别是选自氢及C1-C8烷基；L is selected from bond linkage, -O-, -C(=O)-, -OC(=O)-, -C(=O)O-, -OC(=O)O-, -OC(=O)O-, -S(O) m -, -NR x -, -C(=O)NHR x -, -NHR x C(=O)-, -NR x S(O) m -, S(O) m NR x - and -N[S(O) m R x ]S(O) m -; wherein m is selected from 0, 1 and -2 at each occurrence; and R x is selected from hydrogen at each occurrence and C 1 -C 8 alkyl; Ra在各次出现时分别是选自：R a at each occurrence is selected from: (i)氢、卤原子、氰基及硝基；以及(i) hydrogen, halogen, cyano and nitro; and (ii)C1-C8烷基、C2-C8烯基、C2-C8炔基、C2-C8烷基醚、3元至10元杂环、一-(C1-C8烷基)氨基及二-(C1-C8烷基)氨基及(3元至10元杂环)C1-C6烷基，其各自为未经取代或被1至9个分别选自Rb的取代基取代；以及(ii) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 2 -C 8 alkyl ether, 3- to 10-membered heterocycle, one-(C 1 - C 8 alkyl) amino and di-(C 1 -C 8 alkyl) amino and (3-membered to 10-membered heterocycle) C 1 -C 6 alkyl, each of which is unsubstituted or replaced by 1 to 9, respectively is substituted with a substituent selected from R b ; and Rb在各次出现时分别是选自羟基、卤原子、氨基、氨基羰基、酰氨基、氰基、硝基、酮基、C1-C8烷基、C1-C8烷氧基、C1-C8烷硫基、C1-C8烷基醚、羟基C1-C8烷基、卤基C1-C8烷基、苯基、苯基(C1-C8烷基)、一-(C1-C6烷基)氨基及二-(C1-C6烷基)氨基、(SO2)C1-C8烷基、5元至7元杂环及(5元至7元杂环)(C1-C8烷基)。R b is selected from hydroxyl, halogen atom, amino, aminocarbonyl, amido, cyano, nitro, ketone, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 1 -C 8 alkyl ether, hydroxy C 1 -C 8 alkyl, halo C 1 -C 8 alkyl, phenyl, phenyl (C 1 -C 8 alkyl ), one-(C 1 -C 6 alkyl) amino and di-(C 1 -C 6 alkyl) amino, (SO 2 ) C 1 -C 8 alkyl, 5- to 7-membered heterocycle and (5 membered to 7-membered heterocycle) (C 1 -C 8 alkyl). 2.如权利要求1所述的化合物，其中V为N。2. The compound of claim 1, wherein V is N. 3.如权利要求1所述的化合物，其中X为N。3. The compound of claim 1, wherein X is N. 4.如权利要求3所述的化合物，其中V为N。4. The compound of claim 3, wherein V is N. 5.如权利要求3所述的化合物，其中U为N。5. The compound of claim 3, wherein U is N. 6.如权利要求1所述的化合物，其中W、Y及Z各自分别为N或CH。6. The compound of claim 1, wherein each of W, Y and Z is N or CH, respectively. 7.如权利要求6所述的化合物，其中W及Y各自为CH而Z为N，或其中W及Z各自为CH，而Y为N。7. The compound of claim 6, wherein W and Y are each CH and Z is N, or wherein W and Z are each CH and Y is N. 8.如权利要求1所述的化合物，其中Ar2是选自吡啶基、哒嗪基、嘧啶基、吡嗪基、吡咯基、咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、异噻唑基及噻二唑基，其各自为未经取代或被1或2个选自卤原子、氰基、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、C1-C6烷基醚、C1-C6烷酰基、氨基、一-(C1-C6烷基)氨基及二-(C1-C6烷基)氨基的取代基取代。8. The compound of claim 1 , wherein Ar is selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, Thiazolyl, isothiazolyl and thiadiazolyl, each of which is unsubstituted or replaced by 1 or 2 selected from halogen atoms, cyano, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, Hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkyl ether, C 1 -C 6 alkanoyl, amino, mono-(C 1 -C 6 alkyl)amino and di-(C 1 -C 6 alkane Base) Substituents of amino groups are substituted. 9.如权利要求1所述的化合物，其中Ar2为吡啶基、异噁唑基、噻二唑基或吡唑基，其各自为未经取代或被卤原子、C1-C4烷基、或卤代C1-C4烷基取代。9. The compound of claim 1, wherein Ar 2 is pyridyl, isoxazolyl, thiadiazolyl or pyrazolyl, each of which is unsubstituted or halogen atom, C 1 -C 4 alkyl , or halogenated C 1 -C 4 alkyl substituted. 10.如权利要求1所述的化合物，其中Ar1为苯基或吡啶基，任选地被卤原子、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基或卤代C1-C6烷氧基取代。10. The compound of claim 1, wherein Ar 1 is phenyl or pyridyl, optionally replaced by a halogen atom, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 alkoxy substituted. 11.如权利要求1所述的化合物，其中U为CR2。11. The compound of claim 1, wherein U is CR2 . 12.如权利要求11所述的化合物，其中R2为：12. The compound of claim 11, wherein R 2 is: (i)氢或卤原子；或(i) a hydrogen or halogen atom; or (ii)C1-C6烷基、-(CH2)nNH、-(CH2)nNH(C1-C8烷基)、-(CH2)nN(C1-C8烷基)2、-(CH2)n(5元至8元杂环烷基)、-(CH2)nOH或-(CH2)nO(C1-C8烷基)，其各自为未经取代或被1至4个分别选自卤原子、氰基、羟基、氨基、一-(C1-C6烷基)氨基及二-(C1-C6烷基)氨基、C1-C6烷基及卤代C1-C6烷基的取代基取代。(ii) C 1 -C 6 alkyl, -(CH 2 ) n NH, -(CH 2 ) n NH(C 1 -C 8 alkyl), -(CH 2 ) n N(C 1 -C 8 alkane group) 2 , -(CH 2 ) n (5-membered to 8-membered heterocycloalkyl), -(CH 2 ) n OH or -(CH 2 ) n O(C 1 -C 8 alkyl), each of which is Unsubstituted or 1 to 4 groups selected from halogen, cyano, hydroxyl, amino, mono-(C 1 -C 6 alkyl) amino and di-(C 1 -C 6 alkyl) amino, C 1 Substituents of -C 6 alkyl and halogenated C 1 -C 6 alkyl. 13.如权利要求12所述的化合物，其中X及V各自为N。13. The compound of claim 12, wherein X and V are each N. 14.如权利要求13所述的化合物，其中Ar1及Ar2各自为吡啶基，被一个分别选自卤原子、C1-C4烷基、C1-C4卤代烷基及C1-C4烷氧基的取代基取代。14. The compound as claimed in claim 13, wherein Ar 1 and Ar 2 are each pyridyl, and are selected from a halogen atom, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 1 -C respectively 4 alkoxy substituents are substituted. 15.如权利要求1所述的化合物，其中该化合物是选自：15. The compound of claim 1, wherein the compound is selected from: [7-(3-氟-吡啶-2-基)-喹唑啉-4-基]-(5-三氟甲基-吡啶-2-基)-胺；[7-(3-fluoro-pyridin-2-yl)-quinazolin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine; [6-(丙烷-2-磺酰基)-吡啶-3-基]-[7-(3-三氟甲基-1-吡啶-2-基)-喹唑啉-4-基]-胺盐酸盐；[6-(Propane-2-sulfonyl)-pyridin-3-yl]-[7-(3-trifluoromethyl-1-pyridin-2-yl)-quinazolin-4-yl]-amine salt salt; (5-叔丁基-异噁唑-3-基)-(7-吡啶-2-基-喹唑啉-4-基)-胺；(5-tert-butyl-isoxazol-3-yl)-(7-pyridin-2-yl-quinazolin-4-yl)-amine; (5-三氟甲基-吡啶-2-基)-[7-(3-三氟甲基-1-吡啶-2-基)-喹唑啉-4-基]-胺；(5-Trifluoromethyl-pyridin-2-yl)-[7-(3-trifluoromethyl-1-pyridin-2-yl)-quinazolin-4-yl]-amine; (6-氯-吡啶-3-基)-[7-(2-三氟甲基-苯基)-喹唑啉-4-基]-胺；(6-Chloro-pyridin-3-yl)-[7-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine; (6-异丁基-吡啶-3-基)-[7-(3-三氟甲基-苯基-2-基)-喹唑啉-4-基]-胺；(6-isobutyl-pyridin-3-yl)-[7-(3-trifluoromethyl-phenyl-2-yl)-quinazolin-4-yl]-amine; (6-叔丁基-吡啶-3-基)-[2-甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-胺；(6-tert-butyl-pyridin-3-yl)-[2-methyl-7-(3-methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl] -amine; (6-三氟甲基-吡啶-3-基)-[7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-胺；(6-Trifluoromethyl-pyridin-3-yl)-[7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-yl]-amine ; (6-三氟甲基-吡啶-3-基)-[7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-胺；(6-Trifluoromethyl-pyridin-3-yl)-[7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-yl]-amine ; (7-吡啶-2-基-喹唑啉-4-基)-(5-三氟甲基-吡啶-2-基)-胺；(7-pyridin-2-yl-quinazolin-4-yl)-(5-trifluoromethyl-pyridin-2-yl)-amine; [2-氯-7-(2-三氟甲基-苯基)-吡啶并[2，3-d]嘧啶-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-Chloro-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)- amine; [2-甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-Methyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-(6-trifluoromethyl-pyridine-3 -yl)-amine; [2-甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-Methyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [7-(2-三氟甲基-苯基)-喹唑啉-4-基]-(5-三氟甲基-吡啶-2-基)-胺；[7-(2-Trifluoromethyl-phenyl)-quinazolin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine; (6-叔丁基-吡啶-3-基)-7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-吡啶并[3，2-d]嘧啶-4-基]-胺(顺)；(6-tert-butyl-pyridin-3-yl)-7-(3-chloro-pyridin-2-yl)-2-(2,6-dimethyl-morpholin-4-ylmethyl)-pyridine And[3,2-d]pyrimidin-4-yl]-amine (cis); (6-三氟甲基-吡啶-3-基)-[7-(3-三氟甲基-吡啶-2-基)-2-(3，3，5-三甲基-一氮庚环-1-基甲基)-喹唑啉-4-基]胺；(6-trifluoromethyl-pyridin-3-yl)-[7-(3-trifluoromethyl-pyridin-2-yl)-2-(3,3,5-trimethyl-azepane -1-ylmethyl)-quinazolin-4-yl]amine; (R，R)-(6-叔丁基-吡啶-3-基)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；(R, R)-(6-tert-butyl-pyridin-3-yl)-[2-(2,6-dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoromethane Base-pyridin-2-yl)-quinazolin-4-yl]-amine; (R，R)-(6-叔丁基-吡啶-3-基)-7-(3-氯-吡啶-2-基)-[2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-胺；(R, R)-(6-tert-butyl-pyridin-3-yl)-7-(3-chloro-pyridin-2-yl)-[2-(2,6-dimethyl-morpholine-4 -ylmethyl)-quinazolin-4-yl]-amine; (R，R)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；(R, R)-[2-(2,6-Dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline-4 -yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; (R，R)-7-(3-氯-吡啶-2-基)-[2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；(R, R)-7-(3-chloro-pyridin-2-yl)-[2-(2,6-dimethyl-morpholin-4-ylmethyl)-quinazolin-4-yl] -(6-trifluoromethyl-pyridin-3-yl)-amine; (R，R)-7-(3-氯-吡啶-2-基)-[2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-(6-异丙氧基-吡啶-3-基)-胺；(R, R)-7-(3-chloro-pyridin-2-yl)-[2-(2,6-dimethyl-morpholin-4-ylmethyl)-quinazolin-4-yl] -(6-isopropoxy-pyridin-3-yl)-amine; (S，S)-(6-叔丁基-吡啶-3-基)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；(S, S)-(6-tert-butyl-pyridin-3-yl)-[2-(2,6-dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoromethane Base-pyridin-2-yl)-quinazolin-4-yl]-amine; (S，S)-(6-叔丁基-吡啶-3-基)-7-(3-氯-吡啶-2-基)-[2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-胺；(S, S)-(6-tert-butyl-pyridin-3-yl)-7-(3-chloro-pyridin-2-yl)-[2-(2,6-dimethyl-morpholine-4 -ylmethyl)-quinazolin-4-yl]-amine; (S，S)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；(S, S)-[2-(2,6-Dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline-4 -yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; (S，S)-7-(3-氯-吡啶-2-基)-[2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；(S, S)-7-(3-chloro-pyridin-2-yl)-[2-(2,6-dimethyl-morpholin-4-ylmethyl)-quinazolin-4-yl] -(6-trifluoromethyl-pyridin-3-yl)-amine; [2-(1，1-二酮基-1λ6-硫吗啉-4-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(1,1-diketone-1λ6-thiomorpholin-4-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]- (6-trifluoromethyl-pyridin-3-yl)-amine; [2-(1，4-二噁-8-吖-螺[4.5]癸-8-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(1,4-Dioxa-8-acridine-spiro[4.5]dec-8-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline-4- Base]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-(1-甲基-3，4-二氢-1H-异喹啉-2-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline- 4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(5-三氟甲基-吡啶-2-基)-胺；[2-(2,6-Dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(5 -trifluoromethyl-pyridin-2-yl)-amine; [2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺(顺)；[2-(2,6-Dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6 -trifluoromethyl-pyridin-3-yl)-amine (cis); [2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(5-三氟甲基-吡啶-2-基)-胺(顺)；[2-(2,6-Dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(5 -trifluoromethyl-pyridin-2-yl)-amine (cis); [2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(6-三氟甲基-吡啶-3-基)-胺(顺)；[2-(2,6-Dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidine- 4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine (cis); [2-(2-乙基-哌啶-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(2-Ethyl-piperidin-1-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoro Methyl-pyridin-3-yl)-amine; [2-(2-甲基-哌啶-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(2-Methyl-piperidin-1-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoro Methyl-pyridin-3-yl)-amine; [2-(3，3-二甲基-哌啶-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(3,3-Dimethyl-piperidin-1-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6 -trifluoromethyl-pyridin-3-yl)-amine; [2-(3，4-二氢-1H-异喹啉-2-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]- (6-trifluoromethyl-pyridin-3-yl)-amine; [2-(3，5-二甲基-哌啶-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(3,5-Dimethyl-piperidin-1-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6 -trifluoromethyl-pyridin-3-yl)-amine; [2-(3，5-二甲基-哌啶-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(3,5-Dimethyl-piperidin-1-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6 -trifluoromethyl-pyridin-3-yl)-amine; [2-(3-甲基-哌啶-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(3-Methyl-piperidin-1-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoro Methyl-pyridin-3-yl)-amine; [2-(4-甲基-哌啶-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(5-三氟甲基-吡啶-2-基)-胺；[2-(4-Methyl-piperidin-1-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(5-trifluoro Methyl-pyridin-2-yl)-amine; [2-(4-甲基-哌啶-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(4-Methyl-piperidin-1-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoro Methyl-pyridin-3-yl)-amine; [2-(苄基氨基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(Benzylaminomethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl )-amine; [2-(八氢喹啉-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(Octahydroquinolin-1-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl- Pyridin-3-yl)-amine; [2-[(2-甲氧基-苄基氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(2-Methoxy-benzylamino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-tri Fluoromethyl-pyridin-3-yl)-amine; [2-[(4-甲氧基-苄基氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(4-Methoxy-benzylamino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-tri Fluoromethyl-pyridin-3-yl)-amine; [2-[(丙烯基-甲基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(propenyl-methyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl Base-pyridin-3-yl)-amine; [2-[(苄基-环丙基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(Benzyl-cyclopropyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoro Methyl-pyridin-3-yl)-amine; [2-[(苄基-甲基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(Benzyl-methyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl Base-pyridin-3-yl)-amine; [2-[(苄基-甲基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(Benzyl-methyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl Base-pyridin-3-yl)-amine; [2-[(丁基-乙基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(Butyl-ethyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl Base-pyridin-3-yl)-amine; [2-[(丁基-甲基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(Butyl-methyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl Base-pyridin-3-yl)-amine; [2-[(环己基-乙基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(Cyclohexyl-ethyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl Base-pyridin-3-yl)-amine; [2-[(环己基-甲基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(Cyclohexyl-methyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl Base-pyridin-3-yl)-amine; [2-[(环丙基甲基-丙基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(Cyclopropylmethyl-propyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6- Trifluoromethyl-pyridin-3-yl)-amine; [2-[(环丙基甲基-丙基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(Cyclopropylmethyl-propyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6- Trifluoromethyl-pyridin-3-yl)-amine; [2-[(乙基-异丙基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(Ethyl-isopropyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoro Methyl-pyridin-3-yl)-amine; [2-[(己基-甲基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(Hexyl-methyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl -pyridin-3-yl)-amine; [2-[(2，3二氢化茚-1-基-甲基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(2,3 indan-1-yl-methyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl ]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-[(异丙基-甲基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(isopropyl-methyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoro Methyl-pyridin-3-yl)-amine; [2-[(甲基-苯乙基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(Methyl-phenethyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoro Methyl-pyridin-3-yl)-amine; [2-[(甲基-丙基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(Methyl-propyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl Base-pyridin-3-yl)-amine; [2-[(四氢硫吡喃-4-基氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(tetrahydrothiopyran-4-ylamino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6- Trifluoromethyl-pyridin-3-yl)-amine; [2-[3-(2，6-二甲基-吗啉-4-基)-丙基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[3-(2,6-Dimethyl-morpholin-4-yl)-propyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline-4- Base]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-{[(2-氟-苄基)-甲基-氨基]-甲基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-{[(2-fluoro-benzyl)-methyl-amino]-methyl}-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]- (6-trifluoromethyl-pyridin-3-yl)-amine; [2-{[(3-氟-苄基)-甲基-氨基]-甲基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-{[(3-fluoro-benzyl)-methyl-amino]-methyl}-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]- (6-trifluoromethyl-pyridin-3-yl)-amine; [2-{[(吡啶-2-基甲基)-氨基]-甲基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-{[(pyridin-2-ylmethyl)-amino]-methyl}-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6 -trifluoromethyl-pyridin-3-yl)-amine; [2-{[双-(2-甲氧基-乙基)-氨基]-甲基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(5-三氟甲基-吡啶-2-基)-胺；[2-{[bis-(2-methoxy-ethyl)-amino]-methyl}-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl] -(5-trifluoromethyl-pyridin-2-yl)-amine; [2-{[双-(2-甲氧基-乙基)-氨基]-甲基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-{[bis-(2-methoxy-ethyl)-amino]-methyl}-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl] -(6-trifluoromethyl-pyridin-3-yl)-amine; [2-{[乙基-(2-甲基-丙烯基)-氨基]-甲基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-{[Ethyl-(2-methyl-propenyl)-amino]-methyl}-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl] -(6-trifluoromethyl-pyridin-3-yl)-amine; [2-{[甲基-(1-苯基-乙基)-氨基]-甲基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-{[Methyl-(1-phenyl-ethyl)-amino]-methyl}-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl] -(6-trifluoromethyl-pyridin-3-yl)-amine; [2-{[甲基-(1-苯基-丙基)-氨基]-甲基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-{[Methyl-(1-phenyl-propyl)-amino]-methyl}-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl] -(6-trifluoromethyl-pyridin-3-yl)-amine; [2-{[甲基-(2-甲基-苄基)-氨基]-甲基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-{[Methyl-(2-methyl-benzyl)-amino]-methyl}-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl] -(6-trifluoromethyl-pyridin-3-yl)-amine; [2-一氮庚环-1-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-Azepan-1-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridine- 3-yl)-amine; [2-一氮辛环-1-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-Azacycline-1-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridine- 3-yl)-amine; [2-二丙烯基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-Dipropenylaminomethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl) -amine; [2-二丁基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-Dibutylaminomethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl) -amine; [2-二乙基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-Diethylaminomethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl) -amine; [2-二己基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-Dihexylaminomethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)- amine; [2-二甲基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-Dimethylaminomethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl) -amine; [2-二戊基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-Dipentylaminomethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl) -amine; [2-二丙基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-Dipropylaminomethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl) -amine; [2-二丙基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-Dipropylaminomethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl) -amine; [2-咪唑-1-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-Imidazol-1-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl )-amine; [2-吗啉-4-基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-Morpholin-4-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-yl]-(6-trifluoro Methyl-pyridin-3-yl)-amine; [2-吗啉-4-基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(6-三氟甲基-吡啶-2-基)-胺；[2-Morpholin-4-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-yl]-(6-trifluoro Methyl-pyridin-2-yl)-amine; [2-吗啉-4-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(5-三氟甲基-吡啶-2-基)-胺；[2-Morpholin-4-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(5-trifluoromethyl-pyridine-2- base)-amine; [2-吗啉-4-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-[4-(2，2，2-三氟-1-甲基-乙基)-苯基]-胺；[2-morpholin-4-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-[4-(2,2,2-trifluoro -1-methyl-ethyl)-phenyl]-amine; [2-吗啉-4-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-Morpholin-4-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridine-3- base)-amine; [2-哌啶-1-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-Piperidin-1-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridine-3- base)-amine; [2-吡咯啶-1-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-Pyrrolidin-1-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridine-3- base)-amine; [2-硫吗啉-4-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-thiomorpholin-4-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridine-3 -yl)-amine; [7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺(顺)；[7-(3-Chloro-pyridin-2-yl)-2-(2,6-dimethyl-morpholin-4-ylmethyl)-quinazolin-4-yl]-(6-trifluoro Methyl-pyridin-3-yl)-amine (cis); [7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-吡啶并[3，2-d]嘧啶-4-基]-(6-三氟甲基-吡啶-3-基)-胺(顺)；[7-(3-chloro-pyridin-2-yl)-2-(2,6-dimethyl-morpholin-4-ylmethyl)-pyrido[3,2-d]pyrimidin-4-yl ]-(6-trifluoromethyl-pyridin-3-yl)-amine (cis); {1-[7-(3-三氟甲基-吡啶-2-基)-4-(6-三氟甲基-吡啶-3-基氨基)-喹唑啉-2-基甲基]-哌啶-4-基}-甲醇；{1-[7-(3-trifluoromethyl-pyridin-2-yl)-4-(6-trifluoromethyl-pyridin-3-ylamino)-quinazolin-2-ylmethyl]- Piperidin-4-yl}-methanol; {1-[7-(3-三氟甲基-吡啶-2-基)-4-(6-三氟甲基-吡啶-3-基氨基)-喹唑啉-2-基甲基]-哌啶-3-基}-甲醇；{1-[7-(3-trifluoromethyl-pyridin-2-yl)-4-(6-trifluoromethyl-pyridin-3-ylamino)-quinazolin-2-ylmethyl]- Piperidin-3-yl}-methanol; 1-[7-(3-三氟甲基-吡啶-2-基)-4-(6-三氟甲基-吡啶-3-基氨基)-喹唑啉-2-基甲基]-哌啶-4-醇；1-[7-(3-Trifluoromethyl-pyridin-2-yl)-4-(6-trifluoromethyl-pyridin-3-ylamino)-quinazolin-2-ylmethyl]-piper Pyridine-4-ol; 1-[7-(3-三氟甲基-吡啶-2-基)-4-(6-三氟甲基-吡啶-3-基氨基)-喹唑啉-2-基甲基]-哌啶-3-醇；1-[7-(3-Trifluoromethyl-pyridin-2-yl)-4-(6-trifluoromethyl-pyridin-3-ylamino)-quinazolin-2-ylmethyl]-piper Pyridine-3-ol; 1-[7-(3-三氟甲基-吡啶-2-基)-4-(6-三氟甲基-吡啶-3-基氨基)-喹唑啉-2-基甲基]-哌啶-4-羧酸酰胺；1-[7-(3-Trifluoromethyl-pyridin-2-yl)-4-(6-trifluoromethyl-pyridin-3-ylamino)-quinazolin-2-ylmethyl]-piper Pyridine-4-carboxylic acid amide; 1-{4-[7-(3-三氟甲基-吡啶-2-基)-4-(6-三氟甲基-吡啶-3-基氨基)-喹唑啉-2-基甲基]-哌嗪-1-基}-乙酮；1-{4-[7-(3-trifluoromethyl-pyridin-2-yl)-4-(6-trifluoromethyl-pyridin-3-ylamino)-quinazolin-2-ylmethyl ]-piperazin-1-yl}-ethanone; 2-{1-[7-(3-三氟甲基-吡啶-2-基)-4-(6-三氟甲基-吡啶-3-基氨基)-喹唑啉-2-基甲基]-哌啶-4-基}-乙醇；2-{1-[7-(3-trifluoromethyl-pyridin-2-yl)-4-(6-trifluoromethyl-pyridin-3-ylamino)-quinazolin-2-ylmethyl ]-piperidin-4-yl}-ethanol; 2-{4-[7-(3-三氟甲基-吡啶-2-基)-4-(6-三氟甲基-吡啶-3-基氨基)-喹唑啉-2-基甲基]-哌嗪-1-基}-乙醇；2-{4-[7-(3-trifluoromethyl-pyridin-2-yl)-4-(6-trifluoromethyl-pyridin-3-ylamino)-quinazolin-2-ylmethyl ]-piperazin-1-yl}-ethanol; (6-叔丁基-吡啶-3-基)-[2-(2-甲氧基-乙基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；(6-tert-butyl-pyridin-3-yl)-[2-(2-methoxy-ethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline-4 -yl]-amine; (6-叔丁基-吡啶-3-基)-[2-异丁氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-胺；(6-tert-butyl-pyridin-3-yl)-[2-isobutoxymethyl-7-(3-methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidine- 4-yl]-amine; (6-叔丁基-吡啶-3-基)-[2-异丁氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-胺；(6-tert-butyl-pyridin-3-yl)-[2-isobutoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d] Pyrimidin-4-yl]-amine; (6-叔丁基-吡啶-3-基)-[2-甲氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-胺；(6-tert-butyl-pyridin-3-yl)-[2-methoxymethyl-7-(3-methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidine-4 -yl]-amine; (6-叔丁基-吡啶-3-基)-[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；(6-tert-butyl-pyridin-3-yl)-[2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine ; (6-叔丁基-吡啶-3-基)-[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-胺；(6-tert-butyl-pyridin-3-yl)-[2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidine -4-yl]-amine; (6-叔丁基-吡啶-3-基)-7-(3-氯-吡啶-2-基)-2-乙氧基甲基-喹唑啉-4-基]-胺；(6-tert-butyl-pyridin-3-yl)-7-(3-chloro-pyridin-2-yl)-2-ethoxymethyl-quinazolin-4-yl]-amine; (6-叔丁基-吡啶-3-基)-7-(3-氯-吡啶-2-基)-2-异丁氧基甲基-吡啶并[2，3-d]嘧啶-4-基]-胺；(6-tert-butyl-pyridin-3-yl)-7-(3-chloro-pyridin-2-yl)-2-isobutoxymethyl-pyrido[2,3-d]pyrimidine-4- Base]-amine; (6-叔丁基-吡啶-3-基)-7-(3-氯-吡啶-2-基)-2-甲氧基甲基-喹唑啉-4-基]-胺；(6-tert-butyl-pyridin-3-yl)-7-(3-chloro-pyridin-2-yl)-2-methoxymethyl-quinazolin-4-yl]-amine; (6-叔丁基-吡啶-3-基)-7-(3-氯-吡啶-2-基)-2-甲氧基甲基-吡啶并[2，3-d]嘧啶-4-基]-胺；(6-tert-butyl-pyridin-3-yl)-7-(3-chloro-pyridin-2-yl)-2-methoxymethyl-pyrido[2,3-d]pyrimidin-4-yl ]-amine; [2-(1-甲基-哌啶-4-基氧基甲基)-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(1-Methyl-piperidin-4-yloxymethyl)-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6 -trifluoromethyl-pyridin-3-yl)-amine; [2-(2-二乙基氨基-乙氧基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(2-Diethylamino-ethoxymethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl Base-pyridin-3-yl)-amine; [2-(2-哌啶-1-基-乙氧基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(2-Piperidin-1-yl-ethoxymethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-tri Fluoromethyl-pyridin-3-yl)-amine; [2-(3-苄氧基-丙基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(3-Benzyloxy-propyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridine- 3-yl)-amine; [2-(3-苄氧基-丙基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-叔丁基-吡啶-3-基)-胺；[2-(3-Benzyloxy-propyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-tert-butyl-pyridine-3 -yl)-amine; [2-(吡啶-3-基甲氧基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(pyridin-3-ylmethoxymethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl- Pyridin-3-yl)-amine; [2-(吡啶-4-基甲氧基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(pyridin-4-ylmethoxymethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl- Pyridin-3-yl)-amine; [2-(四氢吡喃-4-基氧基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(tetrahydropyran-4-yloxymethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl Base-pyridin-3-yl)-amine; [2-苄氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-Benzyloxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)- amine; [2-苄氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(5-三氟甲基-吡啶-2-基)-胺；[2-Benzyloxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)- amine; [2-异丁氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-Isobutoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-(6-trifluoromethyl -pyridin-3-yl)-amine; [2-异丙氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-Isopropoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl) -amine; [2-甲氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-Methoxymethyl-7-(3-methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-(6-trifluoromethyl-pyridine- 3-yl)-amine; [2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-Methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-(6-trifluoromethyl- Pyridin-3-yl)-amine; [2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-Methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-yl]-(6-trifluoromethyl- Pyridin-3-yl)-amine; [2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-Methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)- amine; [2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(5-三氟甲基-吡啶-2-基)-胺；[2-Methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)- amine; [7-(3-氯-吡啶-2-基)-2-乙氧基甲基吡啶并[2，3-d]嘧啶-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[7-(3-Chloro-pyridin-2-yl)-2-ethoxymethylpyrido[2,3-d]pyrimidin-4-yl]-(6-trifluoromethyl-pyridin-3- base)-amine; [7-(3-氯-吡啶-2-基)-2-异丁氧基甲基-吡啶并[2，3-d]嘧啶-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[7-(3-Chloro-pyridin-2-yl)-2-isobutoxymethyl-pyrido[2,3-d]pyrimidin-4-yl]-(6-trifluoromethyl-pyridine- 3-yl)-amine; [7-(3-三氟甲基-吡啶-2-基)-4-(6-三氟甲基-吡啶-3-基氨基)-喹唑啉-2-基]-甲醇；及3-[7-(3-三氟甲基-吡啶-2-基)-4-(6-三氟甲基-吡啶-3-基氨基)-喹唑啉-2-基]-丙-1-醇。[7-(3-trifluoromethyl-pyridin-2-yl)-4-(6-trifluoromethyl-pyridin-3-ylamino)-quinazolin-2-yl]-methanol; and 3- [7-(3-Trifluoromethyl-pyridin-2-yl)-4-(6-trifluoromethyl-pyridin-3-ylamino)-quinazolin-2-yl]-propan-1-ol . 16、一种下式化合物：16. A compound of the formula: 或其医药上可接受的盐，其中：or a pharmaceutically acceptable salt thereof, wherein: V、X、W、Y及Z各自分别为N或CR1，其条件是V及X中的至少一个为N；V, X, W, Y and Z are each independently N or CR 1 with the proviso that at least one of V and X is N; U为N或CR2，但若V及X为N，则U为CR2；U is N or CR 2 , but if V and X are N, then U is CR 2 ; R1在各次出现时分别是选自氢、卤原子、羟基、氨基、C1-C8烷基、卤代C1-C8烷基、C1-C8烷氧基、卤代C1-C8烷氧基及一-(C1-C8烷基)氨基及二-(C1-C8烷基)氨基；R 1 is selected from hydrogen, halogen atom, hydroxyl, amino, C 1 -C 8 alkyl, halogenated C 1 -C 8 alkyl, C 1 -C 8 alkoxy, halogenated C 1 -C 8 alkoxy and mono-(C 1 -C 8 alkyl) amino and di-(C 1 -C 8 alkyl) amino; R2为：(i)氢、卤原子、氰基或-COOH；R 2 is: (i) hydrogen, halogen atom, cyano group or -COOH; (ii)C1-C8烷酰基、C2-C8烷酮或C1-C8氨基甲酸根，其各自为未经取代或被1至9个分别选自Rb的取代基取代；或(ii) C 1 -C 8 alkanoyl, C 2 -C 8 alkanone or C 1 -C 8 carbamate, each of which is unsubstituted or substituted by 1 to 9 substituents respectively selected from R b ; or (iii)如式-Rc-M-A-Ry的基团，其中：(iii) A group of formula -Rc - MARy , wherein: Rc为C0-C3烷基；R c is C 0 -C 3 alkyl; M为键连接、N(Rz)、O、S、SO2、C(＝O)pN(Rz)、N(Rz)C(＝O)p、SO2N(Rz)或N(Rz)SO2，其中p为0或1；M is bond linkage, N(R z ), O, S, SO 2 , C(=O) p N(R z ), N(R z )C(=O) p , SO 2 N(R z ) or N(R z )SO 2 , where p is 0 or 1; A为键连接或C1-C8烷基，任选地被1至3个分别选自Rb的取代基取代；以及A is bonded or C 1 -C 8 alkyl, optionally substituted by 1 to 3 substituents selected from R b respectively; and Ry及Rz若存在则为：R y and R z , if present, are: (a)分别为氢、C1-C8烷基、C2-C8烯基、C2-C8炔基、C6-C10芳基C1-C8烷基、C2-C8烷基醚、C1-C8烷氧基、4元至10元碳环或杂环，或接合至Rc而形成一个4元至10元碳环或杂环，其中各个Ry及Rz分别为未经取代或被1至9个分别选自Rb的取代基取代；或(a) hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 6 -C 10 aryl, C 1 -C 8 alkyl, C 2 -C 8 alkyl ether, C 1 -C 8 alkoxy, 4 to 10 membered carbocyclic or heterocyclic ring, or joined to R c to form a 4 to 10 membered carbocyclic or heterocyclic ring, wherein each of R y and R z are each unsubstituted or substituted by 1 to 9 substituents respectively selected from R b ; or (b)接合而形成一个4元至10元碳环或杂环，其为未经取代或被1至9个分别选自Rb的取代基取代；(b) joined to form a 4- to 10-membered carbocyclic or heterocyclic ring, which is unsubstituted or substituted by 1 to 9 substituents selected from R respectively; Ar1及Ar2分别是选自苯基及5元及6元芳香族杂环，其任选地被1至3个分别选自式LRa群组的取代基取代；Ar 1 and Ar 2 are respectively selected from phenyl and 5-membered and 6-membered aromatic heterocycles, which are optionally substituted by 1 to 3 substituents respectively selected from the group of formula LR a ; L在各自出现时分别是选自键连接、-O-、-C(＝O)-、-OC(＝O)-、-C(＝O)O-、-O-C(＝O)O-、-S(O)m-、-NRx-、-C(＝O)NHRx-、-NHRxC(＝O)-、-NRxS(O)m-、S(O)mNRx-及-N[S(O)mRx]S(O)m-；其中m在各自出现时分别是选自0、1及2；以及Rx在各次出现时分别是选自氢及C1-C8烷基；L is selected from bond linkage, -O-, -C(=O)-, -OC(=O)-, -C(=O)O-, -OC(=O)O-, -OC(=O)O-, -S(O) m -, -NR x -, -C(=O)NHR x -, -NHR x C(=O)-, -NR x S(O) m -, S(O) m NR x - and -N[S(O) m R x ]S(O) m -; wherein m at each occurrence is selected from 0, 1 and 2; and R x at each occurrence is selected from hydrogen and C 1 -C 8 alkyl; Ra在各次出现时分别是选自：R a at each occurrence is selected from: (i)氢、卤原子、氰基及硝基；以及(i) hydrogen, halogen, cyano and nitro; and (ii)C1-C8烷基、C2-C8烯基、C2-C8炔基、C2-C8烷基醚、3元至10元杂环、一-(C1-C8烷基)氨基及二-(C1-C8烷基)氨基及(3元至10元杂环)C1-C6烷基，其各自为未经取代或被1至9个分别选自Rb的取代基取代；(ii) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 2 -C 8 alkyl ether, 3- to 10-membered heterocycle, one-(C 1 - C 8 alkyl) amino and di-(C 1 -C 8 alkyl) amino and (3-membered to 10-membered heterocycle) C 1 -C 6 alkyl, each of which is unsubstituted or replaced by 1 to 9, respectively Substituents selected from R b are substituted; Rb在各次出现时分别是选自羟基、卤原子、氨基、氨基羰基、酰氨基、氰基、硝基、酮基、C1-C8烷基、C1-C8烷氧基、C1-C8烷硫基、C1-C8烷基醚、羟基C1-C8烷基、卤基C1-C8烷基、苯基、苯基(C1-C8烷基)、一-(C1-C6烷基)氨基及二-(C1-C6烷基)氨基、(SO2)C1-C8烷基、5元至7元杂环及(5元至7元杂环)(C1-C8烷基)；以及R b is selected from hydroxyl, halogen atom, amino, aminocarbonyl, amido, cyano, nitro, ketone, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 1 -C 8 alkyl ether, hydroxy C 1 -C 8 alkyl, halo C 1 -C 8 alkyl, phenyl, phenyl (C 1 -C 8 alkyl ), one-(C 1 -C 6 alkyl) amino and di-(C 1 -C 6 alkyl) amino, (SO 2 ) C 1 -C 8 alkyl, 5- to 7-membered heterocycle and (5 7-membered heterocycle) (C 1 -C 8 alkyl); and R7为C1-C8烷基、C2-C8烯基、C2-C8炔基、一-(C1-C8烷基)氨基或二-(C1-C8烷基)氨基或3元至10元杂环，其各自任选地被1至5个分别选自羟基、卤原子、C1-C6烷基、C1-C8烷氧基、C2-C8烷基醚、卤代C1-C8烷基及卤代C1-C8烷氧基的取代基取代。R 7 is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, one - (C 1 -C 8 alkyl) amino or two - (C 1 -C 8 alkyl ) amino group or 3-membered to 10-membered heterocyclic ring, each of which is optionally replaced by 1 to 5 members selected from hydroxyl, halogen atom, C 1 -C 6 alkyl, C 1 -C 8 alkoxy, C 2 -C 8 alkyl ether, halogenated C 1 -C 8 alkyl and halogenated C 1 -C 8 alkoxy substituents. 17.如权利要求16所述的化合物，其中V为N。17. The compound of claim 16, wherein V is N. 18.如权利要求16所述的化合物，其中X为N。18. The compound of claim 16, wherein X is N. 19.如权利要求18所述的化合物，其中V为N。19. The compound of claim 18, wherein V is N. 20.如权利要求18所述的化合物，其中U为N。20. The compound of claim 18, wherein U is N. 21.如权利要求16所述的化合物，其中W、Y及Z各自分别为N或CH。21. The compound of claim 16, wherein each of W, Y and Z is N or CH, respectively. 22.如权利要求21所述的化合物，其中W及Y各自为CH而Z是N，或其中W及Z各自为CH，而Y为N。22. The compound of claim 21, wherein W and Y are each CH and Z is N, or wherein W and Z are each CH and Y is N. 23.如权利要求16所述的化合物，其中Ar2为苯基或吡啶基，其各自任选地被1或2个选自卤原子、氰基、C1-C6烷基及卤代C1-C6烷基的取代基取代。23. The compound of claim 16, wherein Ar is phenyl or pyridyl, each of which is optionally replaced by 1 or 2 selected from halogen atoms, cyano, C 1 -C 6 alkyl and halogenated C Substituents of 1 -C 6 alkyl are substituted. 24.如权利要求16所述的化合物，其中Ar2为苯基，任选地被卤原子、C1-C4烷基或卤代C1-C4烷基取代。24. The compound of claim 16, wherein Ar 2 is phenyl, optionally substituted by halogen atom, C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl. 25.如权利要求16所述的化合物，其中Ar1为苯基或吡啶基，任选地被卤原子、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基或卤代C1-C6烷氧基取代。25. The compound of claim 16, wherein Ar is phenyl or pyridyl, optionally replaced by a halogen atom, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 alkoxy substituted. 26.如权利要求16所述的化合物，其中U为CR2。26. The compound of claim 16, wherein U is CR2 . 27.如权利要求26所述的化合物，其中R2为：27. The compound of claim 26, wherein R is: (i)氢或卤原子；或(i) a hydrogen or halogen atom; or (ii)C1-C6烷基、-(CH2)nNH、-(CH2)nNH(C1-C8烷基)、-(CH2)nN(C1-C8烷基)2、-(CH2)n(5元至8元杂环烷基)、-(CH2)nOH或-(CH2)nO(C1-C8烷基)，其各自为未经取代或被1至4个分别选自卤原子、氰基、羟基、氨基、一-(C1-C6烷基)氨基及二-(C1-C6烷基)氨基、C1-C6烷基及卤代C1-C6烷基的取代基取代。(ii) C 1 -C 6 alkyl, -(CH 2 ) n NH, -(CH 2 ) n NH(C 1 -C 8 alkyl), -(CH 2 ) n N(C 1 -C 8 alkane group) 2 , -(CH 2 ) n (5-membered to 8-membered heterocycloalkyl), -(CH 2 ) n OH or -(CH 2 ) n O(C 1 -C 8 alkyl), each of which is Unsubstituted or 1 to 4 groups selected from halogen, cyano, hydroxyl, amino, mono-(C 1 -C 6 alkyl) amino and di-(C 1 -C 6 alkyl) amino, C 1 Substituents of -C 6 alkyl and halogenated C 1 -C 6 alkyl. 28.如权利要求27所述的化合物，其中X及V各自为N。28. The compound of claim 27, wherein X and V are each N. 29.如权利要求16所述的化合物，其中R7包含直接键连接至SO2的氮原子。29. The compound of claim 16, wherein R 7 comprises a nitrogen atom directly bonded to SO 2 . 30.如权利要求29所述的化合物，其中R7为氨基、一-(C1-C6烷基)氨基或二-(C1-C6烷基)氨基、吗啉基、哌啶基、哌嗪基或吡咯啶基，其各自为未经取代或被1至3个分别选自卤原子、C1-C6烷基及卤代C1-C6烷基的取代基取代。30. The compound of claim 29, wherein R 7 is amino, one-(C 1 -C 6 alkyl) amino or two-(C 1 -C 6 alkyl) amino, morpholinyl, piperidinyl , piperazinyl or pyrrolidinyl, each of which is unsubstituted or substituted by 1 to 3 substituents selected from halogen atoms, C 1 -C 6 alkyl and halogenated C 1 -C 6 alkyl. 31.如权利要求16所述的化合物，其中R7为C1-C6烷基、卤代C1-C6烷基、吗啉基、哌啶基、哌嗪基或吡咯啶基，其任选地被1至5个分别选自C1-C6烷基、C1-C6烷氧基、C1-C6烷基醚、卤代C1-C6烷基及卤代C1-C6烷氧基的取代基取代。31. The compound of claim 16, wherein R 7 is C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, morpholinyl, piperidinyl, piperazinyl or pyrrolidinyl, which Optionally 1 to 5 are selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl ether, halogenated C 1 -C 6 alkyl and halogenated C Substituents of 1 -C 6 alkoxy groups are substituted. 32.如权利要求31所述的化合物，其中Ar1及Ar2各自为吡啶基，被一个分别选自卤原子、C1-C4烷基、C1-C4卤代烷基及C1-C4烷氧基的取代基取代。32. The compound as claimed in claim 31, wherein Ar 1 and Ar 2 are each pyridyl, and are independently selected from a halogen atom, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 1 -C 4 alkoxy substituents are substituted. 33.如权利要求16所述的化合物，其中该化合物是选自：33. The compound of claim 16, wherein the compound is selected from: [6-(丙烷-2-磺酰基)-吡啶-3-基]-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺盐酸盐；(1-{4-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基氨基]-苯磺酰基}-吡咯啶-2-基)-甲醇(手性)；(1-{4-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基氨基]-苯磺酰基}-吡咯啶-2-基)-甲醇(手性)；(4-甲烷磺酰基-苯基)-[2-甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-胺；(4-甲烷磺酰基)-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；(4-叔丁基-3-乙烯基-苯基)-[7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-胺；(4-三氟甲烷磺酰基-苯基)-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；(4-三氟甲烷磺酰基-苯基)-[7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-胺；[2-甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲烷磺酰基-苯基)-胺；[4-(2，5-二甲基-吡咯啶-1-磺酰基)-苯基]-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；[4-(2，6-二甲基-吗啉-4-磺酰基)-苯基]-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；[4-(2，6-二甲基-哌啶1-磺酰基)-苯基]-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺(手性)；[4-(2-甲氧基甲基-吡咯啶-1-基-磺酰基)-苯基]-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺(手性)；[4-(2-甲氧基甲基-吡咯啶-1-磺酰基)-苯基]-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺(手性)；[4-(2-甲基-哌啶-1-磺酰基)-苯基]-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；[4-(2-甲基-吡咯啶-1-磺酰基)-苯基]-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；[4-(3-二甲基氨基-吡咯啶-1-磺酰基)-苯基]-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；[4-(3-二甲基氨基-吡咯啶-1-基-磺酰基)-苯基]-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；[4-(4-氟-哌啶-1-磺酰基)-苯基]-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；[4-(4-甲基-哌嗪-1-磺酰基)-苯基]-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；[4-(吗啉-4-磺酰基)-苯基]-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；[4-(吗啉-4-磺酰基)-苯基]-[7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-胺；[4-(哌啶-1-磺酰基)-苯基]-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；[4-(丙烷-1-磺酰基)-苯基]-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；[4-(吡咯啶-1-磺酰基)-苯基]-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；1-{4-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基氨基]-苯磺酰基}-吡咯啶-3-醇(对手性)；4-[4-(吖丁啶-1-磺酰基)-苯基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；N-(2-羟基-1，1-二甲基-乙基)-4-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基氨基]-苯磺酰胺；N-(3-氯-丙基)-4-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基氨基]-苯磺酰胺；N，N-双-(2-甲氧基-乙基)-4-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基氨基]-苯磺酰胺；N，N-二异丙基-4-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基氨基]-苯磺酰胺；N，N-二甲基-4-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基氨基]-苯磺酰胺；N-异丙基-4-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基氨基]-苯磺酰胺；N-叔丁基-4-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基氨基]-苯磺酰胺；N-叔丁基-N-甲基-4-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基氨基]-苯磺酰胺；(R，R)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-[4-(丙烷-2-磺酰基)-苯基]-胺；(R，R)-[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-[4-(丙烷-2-磺酰基)-苯基]-胺；(S)-[7-(3-氯-吡啶-2-基)-[2-(甲基-吗啉-4-基甲基)-喹唑啉-4-基]-[4-(丙烷-2-磺酰基)-苯基]-胺；(S，S)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-[4-(丙烷-2-磺酰基)-苯基]-胺；(S，S)-[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-[4-(丙烷-2-磺酰基)-苯基]-胺；[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲烷磺酰基-苯基)-胺；[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲烷磺酰基-苯基)-胺(顺)；[2-(2，6-二甲基-吗啉-4-基甲基)-[7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(4-甲烷磺酰基-苯基)-胺(顺)；[2-(2，6-二甲基-吗啉-4-基甲基)-[7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(4-三氟甲烷磺酰基-苯基)-胺(顺)；[2-(2，6-二甲基-吗啉-4-基甲基)-[7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-[4-(丙烷-1-磺酰基)-苯基]-胺(顺)；[2-(2，6-二甲基-吗啉-4-基甲基)-[7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-[4-(丙烷-2-磺酰基-)苯基]-胺(顺)；[2-[(乙基-丙基-氨基)-甲基]-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-[4-(吗啉-4-磺酰基)-苯基]-胺；[2-[(异丙基-甲基-氨基)-甲基]-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-[4-(吗啉-4-磺酰基)-苯基]-胺；[2-[(甲基-丙基-氨基)-甲基]-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-[4-(吗啉-4-磺酰基)-苯基]-胺；[2-二甲基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-[4-(吗啉-4-磺酰基)-苯基]-胺；[2-吗啉-4-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲烷磺酰基-苯基)-胺；[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-(4-三氟甲烷磺酰基-苯基)-胺(顺)；[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-吡啶并[3，2-d]嘧啶-4-基]-(4-三氟甲烷磺酰基-苯基)-胺(顺)；[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-吡啶并[3，2-d]嘧啶-4-基]-[4-(吗啉-4-磺酰基)-苯基]-胺；(4-甲烷磺酰基-苯基)-[2-甲氧基甲基-7-(3-氯-吡啶-2-基)-喹唑啉-4-基]-胺；(4-甲烷磺酰基-苯基)-[2-甲氧基甲基-7-(3-氯-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-胺；[2-苄氧基甲基-7-(3-氯-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲烷磺酰基-苯基)-胺；[2-苄氧基甲基-7-(3-氯-吡啶-2-基)-喹唑啉-4-基]-(4-甲烷磺酰基-苯基)-胺；[2-苄氧基甲基-7-(3-三氟-吡啶-2-基)-喹唑啉-4-基]-(1-甲烷磺酰基-2，3-二氢-1H-吲哚-5-基)-胺；[2-环戊氧基甲基-7-(3-氯-吡啶-2-基)-喹唑啉-4-基]-[4-(吗啉-4-磺酰基)-苯基]-胺；[2-环丙基甲氧基甲基-7-(3-氯-吡啶-2-基)-喹唑啉-4-基]-[4-(吗啉-4-磺酰基)-苯基]-胺；[2-乙氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲烷磺酰基-苯基)-胺；[2-异丁氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-甲烷磺酰基-苯基)-胺；[2-异丁氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲烷磺酰基-苯基)-胺；[2-异丁氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-甲烷磺酰基-苯基]-胺；[2-异丁氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-[4-(吗啉-4-磺酰基)-苯基]-胺；[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲烷磺酰基-苯基)-胺；[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲烷磺酰基-苯基)-胺；[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-[4-(吗啉-4-磺酰基)-苯基]-胺；[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲烷磺酰基-苯基)-胺；[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-[4-(吗啉-4-磺酰基)-苯基)-胺；[4-(吗啉-4-磺酰基)-苯基]-[2-(四氢-吡喃-4-基氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；[4-[4-(哌啶-1-磺酰基)-苯基氨基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基]-甲醇；[4-[4-(哌啶-1-磺酰基)-苯基氨基]-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-2-基]-甲醇；7-(3-氯-吡啶-2-基)-2-乙氧基甲基-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲烷磺酰基-苯基)-胺；7-(3-氯-吡啶-2-基)-2-异丁氧基甲基-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲烷磺酰基-苯基)-胺；7-(3-氯-吡啶-2-基)-2-甲氧基甲基-吡啶并[2，3-d]嘧啶-4-基]-[4-(吗啉-4-磺酰基)-苯基]-胺；4-[2-苄氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基氨基]-N-叔丁基-苯磺酰胺；N-叔丁基-4-[2-羟基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基氨基]-N-甲基-苯磺酰胺；N-叔丁基-4-[2-羟基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基氨基]-N-甲基-苯磺酰胺以及N-叔丁基-4-[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基氨基]-苯磺酰胺。[6-(Propane-2-sulfonyl)-pyridin-3-yl]-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine hydrochloride ; (1-{4-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-ylamino]-benzenesulfonyl}-pyrrolidin-2-yl)-methanol ( chiral); (1-{4-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-ylamino]-benzenesulfonyl}-pyrrolidin-2-yl) - methanol (chiral); (4-methanesulfonyl-phenyl)-[2-methyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d] Pyrimidin-4-yl]-amine; (4-methanesulfonyl)-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine; (4-tert Butyl-3-vinyl-phenyl)-[7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-yl]-amine; (4 -trifluoromethanesulfonyl-phenyl)-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine; (4-trifluoromethanesulfonyl-benzene Base)-[7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-yl]-amine; [2-methyl-7-(3- Trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine; [4-(2,5 -Dimethyl-pyrrolidine-1-sulfonyl)-phenyl]-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine; [4- (2,6-Dimethyl-morpholine-4-sulfonyl)-phenyl]-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine ; [4-(2,6-Dimethyl-piperidine 1-sulfonyl)-phenyl]-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl ]-amine (chiral); [4-(2-methoxymethyl-pyrrolidin-1-yl-sulfonyl)-phenyl]-[7-(3-trifluoromethyl-pyridine-2- Base)-quinazolin-4-yl]-amine (chiral); [4-(2-methoxymethyl-pyrrolidine-1-sulfonyl)-phenyl]-[7-(3-tri Fluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine (chiral); [4-(2-methyl-piperidine-1-sulfonyl)-phenyl]-[7 -(3-Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine; [4-(2-Methyl-pyrrolidine-1-sulfonyl)-phenyl]-[ 7-(3-Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine; [4-(3-Dimethylamino-pyrrolidine-1-sulfonyl)-phenyl ]-[7-(3-Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine; [4-(3-Dimethylamino-pyrrolidin-1-yl-sulfonate Acyl)-phenyl]-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine; [4-(4-fluoro-piperidine-1-sulfonic Acyl)-phenyl]-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine; [4-(4-methyl-piperazine-1- Sulfonyl)-phenyl]-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine; [4-(morpholine-4-sulfonyl)- Phenyl]-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine; [4-(morpholine-4-sulfonyl)-phenyl]- [7-(3-Trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-yl]-amine; [4-(piperidine-1-sulfonyl)-benzene Base]-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine; [4-(propane-1-sulfonyl)-phenyl]-[7 -(3-Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine; [4-(pyrrolidine-1-sulfonyl)-phenyl]-[7-(3- Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine; 1-{4-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin- 4-ylamino]-benzenesulfonyl}-pyrrolidin-3-ol (chiral); 4-[4-(azetidine-1-sulfonyl)-phenyl]-7-(3-trifluoromethyl Base-pyridin-2-yl)-quinazolin-4-yl]-amine; N-(2-hydroxy-1,1-dimethyl-ethyl)-4-[7-(3-trifluoromethane Base-pyridin-2-yl)-quinazolin-4-ylamino]-benzenesulfonamide; N-(3-chloro-propyl)-4-[7-(3-trifluoromethyl-pyridine-2 -yl)-quinazolin-4-ylamino]-benzenesulfonamide; N,N-bis-(2-methoxy-ethyl)-4-[7-(3-trifluoromethyl-pyridine- 2-yl)-quinazolin-4-ylamino]-benzenesulfonamide; N,N-diisopropyl-4-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazole Lin-4-ylamino]-benzenesulfonamide; N,N-Dimethyl-4-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-ylamino]- Benzenesulfonamide; N-isopropyl-4-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-ylamino]-benzenesulfonamide; N-tert-butyl- 4-[7-(3-Trifluoromethyl-pyridin-2-yl)-quinazolin-4-ylamino]-benzenesulfonamide; N-tert-butyl-N-methyl-4-[7- (3-Trifluoromethyl-pyridin-2-yl)-quinazolin-4-ylamino]-benzenesulfonamide; (R,R)-[2-(2,6-Dimethyl-morpholine- 4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-[4-(propane-2-sulfonyl)-phenyl]-amine ; (R, R)-[7-(3-chloro-pyridin-2-yl)-2-(2,6-dimethyl-morpholin-4-ylmethyl)-quinazolin-4-yl ]-[4-(propane-2-sulfonyl)-phenyl]-amine; (S)-[7-(3-chloro-pyridin-2-yl)-[2-(methyl-morpholine-4 -ylmethyl)-quinazolin-4-yl]-[4-(propane-2-sulfonyl)-phenyl]-amine; (S,S)-[2-(2,6-dimethyl -Morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-[4-(propane-2-sulfonyl)-benzene base]-amine; (S,S)-[7-(3-chloro-pyridin-2-yl)-2-(2,6-dimethyl-morpholin-4-ylmethyl)-quinazoline -4-yl]-[4-(propane-2-sulfonyl)-phenyl]-amine; [2-(2,6-dimethyl-morpholin-4-ylmethyl)-7-(3 -trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine; [2-(2,6-dimethyl-methanol Lin-4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine ( cis); [2-(2,6-dimethyl-morpholin-4-ylmethyl)-[7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2- d] pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amine (cis); [2-(2,6-dimethyl-morpholin-4-ylmethyl)-[7- (3-Trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine (cis); [ 2-(2,6-Dimethyl-morpholin-4-ylmethyl)-[7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidine- 4-yl]-[4-(propane-1-sulfonyl)-phenyl]-amine (cis); [2-(2,6-dimethyl-morpholin-4-ylmethyl)-[7 -(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-yl]-[4-(propane-2-sulfonyl-)phenyl]-amine ( cis); [2-[(Ethyl-propyl-amino)-methyl]-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-[4 -(morpholine-4-sulfonyl)-phenyl]-amine; [2-[(isopropyl-methyl-amino)-methyl]-[7-(3-trifluoromethyl-pyridine-2 -yl)-quinazolin-4-yl]-[4-(morpholine-4-sulfonyl)-phenyl]-amine; [2-[(methyl-propyl-amino)-methyl]- [7-(3-Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-[4-(morpholine-4-sulfonyl)-phenyl]-amine; [2-di Methylaminomethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-[4-(morpholine-4-sulfonyl)-phenyl]-amine ; [2-morpholin-4-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethanesulfonyl-phenyl )-amine; [7-(3-chloro-pyridin-2-yl)-2-(2,6-dimethyl-morpholin-4-ylmethyl)-quinazolin-4-yl]-( 4-Trifluoromethanesulfonyl-phenyl)-amine (cis); [7-(3-chloro-pyridin-2-yl)-2-(2,6-dimethyl-morpholin-4-ylmethyl Base)-pyrido[3,2-d]pyrimidin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine (cis); [7-(3-chloro-pyridin-2-yl )-2-(2,6-dimethyl-morpholin-4-ylmethyl)-pyrido[3,2-d]pyrimidin-4-yl]-[4-(morpholine-4-sulfonyl )-phenyl]-amine; (4-methanesulfonyl-phenyl)-[2-methoxymethyl-7-(3-chloro-pyridin-2-yl)-quinazolin-4-yl] -amine; (4-methanesulfonyl-phenyl)-[2-methoxymethyl-7-(3-chloro-pyridin-2-yl)-pyrido[2,3-d]pyrimidine-4- Base]-amine; [2-Benzyloxymethyl-7-(3-chloro-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)- Amine; [2-benzyloxymethyl-7-(3-chloro-pyridin-2-yl)-quinazolin-4-yl]-(4-methanesulfonyl-phenyl)-amine; [2- Benzyloxymethyl-7-(3-trifluoro-pyridin-2-yl)-quinazolin-4-yl]-(1-methanesulfonyl-2,3-dihydro-1H-indole-5 -yl)-amine; [2-cyclopentyloxymethyl-7-(3-chloro-pyridin-2-yl)-quinazolin-4-yl]-[4-(morpholine-4-sulfonyl )-phenyl]-amine; [2-cyclopropylmethoxymethyl-7-(3-chloro-pyridin-2-yl)-quinazolin-4-yl]-[4-(morpholine- 4-sulfonyl)-phenyl]-amine; [2-ethoxymethyl-7-(3-methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl ]-(4-trifluoromethanesulfonyl-phenyl)-amine; [2-isobutoxymethyl-7-(3-methyl-pyridin-2-yl)-pyrido[2,3-d ]pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amine; [2-isobutoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido [2,3-d]pyrimidin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine; [2-isobutoxymethyl-7-(3-trifluoromethyl-pyridine -2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-(4-methanesulfonyl-phenyl]-amine; [2-isobutoxymethyl-7-(3- Trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-[4-(morpholine-4-sulfonyl)-phenyl]-amine; [2- Methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-(4-trifluoromethanesulfonyl-phenyl )-amine; [2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-(4-tri Fluoromethanesulfonyl-phenyl)-amine; [2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidine-4- Base]-[4-(morpholine-4-sulfonyl)-phenyl]-amine; [2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazole Lin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine; [2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazole Line-4-yl]-[4-(morpholine-4-sulfonyl)-phenyl)-amine; [4-(morpholine-4-sulfonyl)-phenyl]-[2-(tetrahydro- Pyran-4-yloxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine; [4-[4-(piperidine-1 -sulfonyl)-phenylamino]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-yl]-methanol; [4-[4-(piperidine-1- Sulfonyl)-phenylamino]-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-2-yl]-methanol; 7-(3-chloro -pyridin-2-yl)-2-ethoxymethyl-pyrido[2,3-d]pyrimidin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine; 7-( 3-Chloro-pyridin-2-yl)-2-isobutoxymethyl-pyrido[2,3-d]pyrimidin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine ; 7-(3-Chloro-pyridin-2-yl)-2-methoxymethyl-pyrido[2,3-d]pyrimidin-4-yl]-[4-(morpholine-4-sulfonyl )-phenyl]-amine; 4-[2-benzyloxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-ylamino]-N-tert-butyl Base-benzenesulfonamide; N-tert-butyl-4-[2-hydroxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-ylamino]-N- Methyl-benzenesulfonamide; N-tert-butyl-4-[2-hydroxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidine- 4-ylamino]-N-methyl-benzenesulfonamide and N-tert-butyl-4-[2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinone Azolin-4-ylamino]-benzenesulfonamide. 34、一种如下式的化合物：34. A compound of the formula:
Figure A038024520020C1
Figure A038024520020C1
 其中：in: V、X、W、Y及Z各自分别为N或CR1，其条件是V及X中的至少一个为N；V, X, W, Y and Z are each independently N or CR 1 with the proviso that at least one of V and X is N; R1在各次出现时分别是选自氢、卤原子、羟基、氰基、氨基、C1-C8烷基、卤代C1-C8烷基、C1-C8烷氧基、卤代C1-C8烷氧基及一-(C1-C6烷基)氨基及二-(C1-C6烷基)氨基；R 1 is selected from hydrogen, halogen atom, hydroxyl, cyano, amino, C 1 -C 8 alkyl, halogenated C 1 -C 8 alkyl, C 1 -C 8 alkoxy, Halogenated C 1 -C 8 alkoxy and mono-(C 1 -C 6 alkyl)amino and di-(C 1 -C 6 alkyl)amino; Ar1及Ar2分别是选自苯基及5元至7元芳香族杂环，其各自为未经取代或被1至3个分别选自式LRa群组的取代基取代；Ar 1 and Ar 2 are respectively selected from phenyl and 5-7 membered aromatic heterocycles, each of which is unsubstituted or substituted by 1 to 3 substituents selected from the group of formula LRa ; L在各自出现时分别是选自键连接、-O-、-C(＝O)-、-OC(＝O)-、-C(＝O)O-、-O-C(＝O)O-、-S(O)m-、-NRx-、-C(＝O)NHRx-、-NHRxC(＝O)-、-NRxS(O)m-、S(O)mNRx-及-N[S(O)mRx]S(O)m-；其中m在各自出现时分别是选自0、1及2；以及Rx在各次出现时分别是选自氢及C1-C8烷基；L is selected from bond linkage, -O-, -C(=O)-, -OC(=O)-, -C(=O)O-, -OC(=O)O-, -OC(=O)O-, -S(O) m -, -NR x -, -C(=O)NHR x -, -NHR x C(=O)-, -NR x S(O) m -, S(O) m NR x - and -N[S(O) m R x ]S(O) m -; wherein m at each occurrence is selected from 0, 1 and 2; and R x at each occurrence is selected from hydrogen and C 1 -C 8 alkyl; Ra在各次出现时分别是选自：R a at each occurrence is selected from: (i)氢、卤原子、氰基及硝基；以及(i) hydrogen, halogen, cyano and nitro; and (ii)C1-C8烷基、C2-C8烯基、C2-C8炔基、C2-C8烷基醚、3元至10元杂环、及(3元至10元杂环)C1-C6烷基，其各自为未经取代或被1至9个分别选自Rb的取代基取代；(ii) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 2 -C 8 alkyl ether, 3-10-membered heterocycle, and (3-10 membered heterocycle) C 1 -C 6 alkyl, each of which is unsubstituted or substituted by 1 to 9 substituents respectively selected from R b ; R3及R4为：R 3 and R 4 are: (i)各自分别是选自(i) are each selected from (a)氢；(a) hydrogen; (b)C1-C8烷基、C2-C8烯基、C2-C8炔基、C1-C8烷氧基、C3-C8烷酮、C2-C8烷酰基、C2-C8烷基醚、C6-C10芳基C0-C8烷基、5元至10元杂环C0-C8烷基及-(SO2)C1-C8烷基，其各自任选地被1至9个分别选自Rb的取代基取代；以及(b) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 alkoxy, C 3 -C 8 alkanone, C 2 -C 8 alkane Acyl, C 2 -C 8 alkyl ether, C 6 -C 10 aryl C 0 -C 8 alkyl, 5- to 10-membered heterocycle C 0 -C 8 alkyl and -(SO 2 )C 1 -C 8 alkyl groups, each of which is optionally substituted by 1 to 9 substituents respectively selected from R ; and (c)接合至R5或R6而形成一个4元至10元杂环基的基团，其为未经取代或被1至6个分别选自Rb的取代基取代；或(c) bonded to R or R to form a 4- to 10-membered heterocyclyl group, which is unsubstituted or substituted by 1 to 6 substituents selected from R respectively; or (ii)与其键连接至N接合而形成一个4元至10元杂环，其为未经取代或被1至6个分别选自Rb、C1-C8烷酰基、4元至7元杂环烷基C0-C4烷基、及一-及二-(C1-C6烷基)氨基C1-C6烷基的取代基取代；(ii) It is bonded to N to form a 4-10-membered heterocyclic ring, which is unsubstituted or replaced by 1 to 6 members selected from R b , C 1 -C 8 alkanoyl, 4-7 membered Heterocycloalkyl C 0 -C 4 alkyl, and mono- and di-(C 1 -C 6 alkyl) amino C 1 -C 6 alkyl are substituted by substituents; R5及R6在各次出现时分别为：R 5 and R 6 are respectively: (i)各自分别选自：(i) each selected from: (a)氢或羟基；(a) hydrogen or hydroxyl; (b)C1-C8烷基，其为未经取代或被1至2个分别选自Rb的取代基取代；以及(b) C 1 -C 8 alkyl, which is unsubstituted or substituted by 1 to 2 substituents respectively selected from R b ; and (c)基团其是接合至R5或R6而形成一个4元至10元杂环族，其为未经取代或被1至6个分别选自Rb的取代基取代；(c) a group which is bonded to R or R to form a 4- to 10 -membered heterocyclic group, which is unsubstituted or substituted by 1 to 6 substituents respectively selected from R ; (ii)共同结合而形成一个酮基；或(ii) combined to form a keto group; or (iii)接合而形成一个3元至7元碳环环或杂环环，其为未经取代或被1至4个选自Rb的取代基取代；(iii) joined to form a 3-7 membered carbocyclic ring or heterocyclic ring, which is unsubstituted or substituted with 1 to 4 substituents selected from R ; Rb在各次出现时分别是选自羟基、卤原子、氨基、氨基羰基、酰氨基、氰基、硝基、酮基、C1-C8烷基、C1-C8烷氧基、C1-C8烷硫基、C1-C8烷基醚、羟基C1-C8烷基、卤基C1-C8烷基、苯基、苯基(C1-C8烷基)、一-(C1-C6烷基)氨基及二-(C1-C6烷基)氨基、(SO2)C1-C8烷基、5元至7元杂环及(5元至7元杂环)(C1-C8烷基)；以及R b is selected from hydroxyl, halogen atom, amino, aminocarbonyl, amido, cyano, nitro, ketone, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 1 -C 8 alkyl ether, hydroxy C 1 -C 8 alkyl, halo C 1 -C 8 alkyl, phenyl, phenyl (C 1 -C 8 alkyl ), one-(C 1 -C 6 alkyl) amino and di-(C 1 -C 6 alkyl) amino, (SO 2 ) C 1 -C 8 alkyl, 5- to 7-membered heterocycle and (5 7-membered heterocycle) (C 1 -C 8 alkyl); and n为1、2或3。n is 1, 2 or 3. 35.如权利要求34所述的化合物或盐，其中V及X皆为N。35. The compound or salt of claim 34, wherein V and X are both N. 36.如权利要求34所述的化合物或盐，其中W为N而Y与Z为CH。36. The compound or salt of claim 34, wherein W is N and Y and Z are CH. 37.如权利要求34所述的化合物或盐，其中Y为N而W与Z为CH。37. The compound or salt of claim 34, wherein Y is N and W and Z are CH. 38.如权利要求34所述的化合物或盐，其中Z为N而W与Y为CH。38. The compound or salt of claim 34, wherein Z is N and W and Y are CH. 39.如权利要求34所述的化合物或盐，其中W、Y及Z各自为CH。39. The compound or salt of claim 34, wherein W, Y and Z are each CH. 40.如权利要求34所述的化合物或盐，其中Ar1及Ar2分别是选自苯基及6元芳香族杂环，其各自被0、1或2个取代基取代。40. The compound or salt of claim 34, wherein Ar 1 and Ar 2 are respectively selected from phenyl and 6-membered aromatic heterocycles, each of which is substituted by 0, 1 or 2 substituents. 41.如权利要求40所述的化合物或盐，其中：41. The compound or salt of claim 40, wherein: (i)Ar1为苯基或吡啶基，其各自为未经取代或被1或2个选自卤原子、羟基、氰基、氨基、硝基、一-(C1-C6烷基)氨基及二-(C1-C6烷基)氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基及卤代C1-C6烷氧基的取代基取代；以及(i) Ar is phenyl or pyridyl, each of which is unsubstituted or replaced by 1 or 2 selected from halogen atoms, hydroxyl, cyano, amino, nitro, one-(C 1 -C 6 alkyl) Amino and di-(C 1 -C 6 alkyl) amino, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy and halogenated C 1 -C 6 alkane substituent substitution of oxy; and (ii)Ar2为苯基或吡啶基，其各自为未经取代或被1或2个分别选自卤原子、羟基、氰基、氨基、一-(C1-C6烷基)氨基及二-(C1-C6烷基)氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C2-C6烷基醚，C1-C6烷酰基、-(SO2)R2、-NRxS(O)m-及-N(S(Om)2的取代基取代；其中m为1或2，Rx为氢或C1-C6烷基以及R2为C1-C6烷基、卤代C1-C6烷基、氨基、一-或二-(C1-C6烷基)氨基或5元至10元N连接杂环基，各个R2任选地被Rb取代。(ii) Ar 2 is phenyl or pyridyl, each of which is unsubstituted or replaced by 1 or 2 selected from halogen atoms, hydroxyl, cyano, amino, one-(C 1 -C 6 alkyl) amino and Di-(C 1 -C 6 alkyl)amino, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy , C 2 -C 6 alkyl ether, C 1 -C 6 alkanoyl, -(SO 2 )R 2 , -NR x S(O) m -and -N(S(O m ) 2 substituents; wherein m is 1 or 2, R x is hydrogen or C 1 -C 6 alkyl and R 2 is C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, amino, mono- or di-(C 1 -C 6 alkyl) amino or 5-10 membered N-linked heterocyclyl, each R 2 is optionally substituted by R b . 42.如权利要求41所述的化合物或盐，其中：42. The compound or salt of claim 41, wherein: (i)Ar1为吡啶基，其为未经取代或被卤原子、C1-C4烷基或卤代C1-C4烷基取代；以及(i) Ar is pyridyl, which is unsubstituted or substituted by a halogen atom, C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl; and (ii)Ar2为苯基或吡啶基，其各自为未经取代或被卤原子、氰基、C1-C4烷基、卤代C1-C4烷基、C2-C4烷基醚、C1-C4烷酰基或-(SO2)Ra取代，其中Ra为C1-C4烷基或卤代C1-C4烷基。(ii) Ar 2 is phenyl or pyridyl, each of which is unsubstituted or replaced by a halogen atom, cyano, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, C 2 -C 4 alkane Substituted by base ether, C 1 -C 4 alkanoyl or -(SO 2 )R a , wherein R a is C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl. 43.如权利要求42所述的化合物或盐，其中：43. The compound or salt of claim 42, wherein: (i)Ar1为吡啶-2-基、3-甲基-吡啶-2-基、3-三氟甲基-吡啶-2-基或3-卤-吡啶-2-基；以及(i) Ar is pyridin-2-yl, 3-methyl-pyridin-2-yl, 3-trifluoromethyl-pyridin-2-yl or 3-halo-pyridin-2-yl; and (ii)Ar2为苯基、2-吡啶基或3-吡啶基，其各自在4位置被三氟甲烷磺酰基、丙烷磺酰基、丙烷-2-磺酰基、叔丁基、三氟甲基或2，2，2-三氟-1-甲基-乙基取代。(ii) Ar 2 is phenyl, 2-pyridyl or 3-pyridyl, each of which is replaced at the 4 position by trifluoromethanesulfonyl, propanesulfonyl, propane-2-sulfonyl, tert-butyl, trifluoromethyl Or 2,2,2-trifluoro-1-methyl-ethyl substitution. 44.如权利要求34所述的化合物或盐，其中R3及R4各自分别为：44. The compound or salt of claim 34, wherein R and R are each: (i)氢；或(i) hydrogen; or (ii)C1-C8烷基、C2-C8烯基、苯基C0-C4烷基、2，3二氢化茚基C0-C4烷基、5元至6元杂芳基C0-C4烷基、或4元至7元杂环烷基C0-C4烷基，其各自为未经取代或被1至4个分别选自羟基、卤原子、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基及卤代C1-C6烷氧基的取代基取代。(ii) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, phenyl C 0 -C 4 alkyl, 2,3 indanyl C 0 -C 4 alkyl, 5-6 membered hetero Aryl C 0 -C 4 alkyl, or 4-membered to 7-membered heterocycloalkyl C 0 -C 4 alkyl, each of which is unsubstituted or replaced by 1 to 4 members selected from hydroxyl, halogen, amino, Substituents of C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy and halogenated C 1 -C 6 alkoxy. 45.如权利要求44所述的化合物或盐，其中R3及R4各自分别为45. The compound or salt as claimed in claim 44, wherein R 3 and R 4 are each respectively (i)氢；或(i) hydrogen; or (ii)C1-C6烷基、C2-C6烯基、5元至7元杂环C0-C4烷基、C2-C6烷基醚、2，3二氢化茚基、苄基、1-苯乙基、1-苯丙基及2-苯乙基，其各自为未经取代或被1至3个分别选自羟基、卤原子及C1-C4烷基的取代基取代。(ii) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, 5-7 membered heterocycle C 0 -C 4 alkyl, C 2 -C 6 alkyl ether, 2,3 indanyl , benzyl, 1-phenethyl, 1-phenylpropyl and 2-phenethyl, each of which is unsubstituted or replaced by 1 to 3 selected from hydroxyl, halogen atom and C 1 -C 4 alkyl Substituents replace. 46.如权利要求44所述的化合物或盐，其中R3及R4之一为吡啶基C0-C4烷基、嘧啶基C0-C4烷基、咪唑基C0-C4烷基或四唑基C0-C4烷基，其各自被0、1或2个取代基取代。46. The compound or salt as claimed in claim 44, wherein one of R and R is pyridyl C 0 -C 4 alkyl , pyrimidinyl C 0 -C 4 alkyl, imidazolyl C 0 -C 4 alkane or tetrazolylC 0 -C 4 alkyl, each of which is substituted by 0, 1 or 2 substituents. 47.如权利要求34所述的化合物或盐，其中R3与R4接合而形成一个5元至10元杂环基，其被0至4个取代基取代。47. The compound or salt of claim 34, wherein R3 and R4 are combined to form a 5- to 10-membered heterocyclic group, which is substituted by 0 to 4 substituents. 48.如权利要求47所述的化合物或盐，其中该杂环基被至少一个选自羟基、卤原子、C1-C4烷基、卤代C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷氧基、C1-C4烷酰基及氨基羰基的取代基取代。48. The compound or salt as claimed in claim 47, wherein the heterocyclic group is replaced by at least one selected from hydroxyl, halogen atom, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, C 1 -C Substituents of 4 alkoxy, halogenated C 1 -C 4 alkoxy, C 1 -C 4 alkanoyl and aminocarbonyl. 49.如权利要求47所述的化合物或盐，其中该杂环基包含一个芳香环。49. The compound or salt of claim 47, wherein the heterocyclyl comprises an aromatic ring. 50.如权利要求49所述的化合物或盐，其中该杂环基为被0、1或2个取代基取代的3，4-二氢-1H-异喹啉-2-基。50. The compound or salt of claim 49, wherein the heterocyclyl is 3,4-dihydro-1H-isoquinolin-2-yl substituted by 0, 1 or 2 substituents. 51.如权利要求47所述的化合物或盐，其中该杂环基为5元至10元杂环烷基，其是被0至4个取代基取代。51. The compound or salt of claim 47, wherein the heterocyclyl is a 5- to 10-membered heterocycloalkyl, which is substituted by 0 to 4 substituents. 52.如权利要求51所述的化合物或盐，其中该杂环烷基为哌啶基、哌嗪基、吡咯啶基、一氮庚环基、一氮辛环基、十氢喹啉基或1，4-二噁-8-吖-螺[4.5]癸-8-基，其各自为未经取代或被1至4个分别选自卤原子、羟基、C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷基、卤代C1-C4烷氧基、C1-C4烷酰基及C1-C4烷氧羰基的取代基取代。52. The compound or salt as claimed in claim 51, wherein the heterocycloalkyl is piperidinyl, piperazinyl, pyrrolidinyl, azepanyl, azaoctyl, decahydroquinolinyl or 1,4-Dioxa-8-acridine-spiro[4.5]dec-8-yl, each of which is unsubstituted or replaced by 1 to 4 selected from halogen atoms, hydroxyl, C 1 -C 4 alkyl, C Substituents of 1 -C 4 alkoxy, halogenated C 1 -C 4 alkyl, halogenated C 1 -C 4 alkoxy, C 1 -C 4 alkanoyl and C 1 -C 4 alkoxycarbonyl. 53.如权利要求51所述的化合物或盐，其中该杂环基为吗啉基、硫吗啉基或1，1-二酮基-硫吗啉-4-基，其各自为未经取代或被1至4个分别选自卤原子、羟基、C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷基、卤代C1-C4烷氧基、C1-C4烷酰基及C1-C4烷氧羰基的取代基取代。53. The compound or salt of claim 51, wherein the heterocyclic group is morpholinyl, thiomorpholinyl or 1,1-diketonyl-thiomorpholin-4-yl, each of which is unsubstituted Or by 1 to 4 selected from halogen atoms, hydroxyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogenated C 1 -C 4 alkyl, halogenated C 1 -C 4 alkoxy Substituents of radical, C 1 -C 4 alkanoyl and C 1 -C 4 alkoxycarbonyl. 54.如权利要求52或53所述的化合物或盐，其中该杂环基是被1至4个分别选自甲基及乙基的取代基取代。54. The compound or salt according to claim 52 or 53, wherein the heterocyclic group is substituted with 1 to 4 substituents selected from methyl and ethyl, respectively. 55.如权利要求34所述的化合物或盐，其中R5及R6各自分别是选自氢及C1-C6烷基。55. The compound or salt of claim 34, wherein R 5 and R 6 are each independently selected from hydrogen and C 1 -C 6 alkyl. 56.如权利要求55所述的化合物或盐，其中R5及R6各自为氢。56. The compound or salt of claim 55, wherein R 5 and R 6 are each hydrogen. 57.如权利要求34所述的化合物或盐，其中n为1。57. The compound or salt of claim 34, wherein n is 1. 58.如权利要求34所述的化合物或盐，其中58. The compound or salt of claim 34, wherein (i)V及X为N；(i) V and X are N; (ii)Ar1为吡啶基，其为未经取代或被卤原子、C1-C4烷基或卤代C1-C4烷基取代；(ii) Ar is pyridyl, which is unsubstituted or substituted by a halogen atom, C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl; (iii)Ar2为苯基或吡啶基，其为未经取代或被C1-C4烷基、卤代C1-C4烷基或式-(SO2)R2基团取代，其中R2为C1-C4烷基或卤代C1-C4烷基；(iii) Ar 2 is phenyl or pyridyl, which is unsubstituted or substituted by C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl or a group of formula -(SO 2 )R 2 , wherein R 2 is C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl; (iv)R3及R4各自分别是选自C1-C6烷基、C2-C6烯基、C2-C6烷基醚、5元至10元杂芳基C0-C4烷基、苯基C0-C4烷基及2，3二氢化茚基，其各自被0、1或2个分别选自羟基、卤原子、C1-C4烷基及卤代C1-C4烷基的取代基取代；以及(iv) R 3 and R 4 are each selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkyl ether, 5- to 10-membered heteroaryl C 0 -C 4 alkyl, phenyl C 0 -C 4 alkyl and 2,3 indanyl, each of which is 0, 1 or 2 selected from hydroxyl, halogen atom, C 1 -C 4 alkyl and halogenated C Substituent substitution of 1 -C 4 alkyl; and (v)n为1。(v) n is 1. 59.如权利要求34所述的化合物或盐，其中：59. The compound or salt of claim 34, wherein: (i)V及X为N；(i) V and X are N; (ii)Ar1为吡啶基，其为未经取代或被卤原子、C1-C4烷基或卤代C1-C4烷基取代；(ii) Ar is pyridyl, which is unsubstituted or substituted by a halogen atom, C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl; (iii)Ar为苯基或吡啶基，其为未经取代或被C1-C4烷基、卤代C1-C4烷基或式-(SO2)R2基团取代，其中R2为C1-C4烷基或卤代C1-C4烷基；(iii) Ar is phenyl or pyridyl, which is unsubstituted or substituted by C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl or a group of formula -(SO 2 )R 2 , wherein R 2 is C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl; (iv)R3及R4接合而形成一个5元至10元杂环基，其为未经取代或(iv) R 3 and R 4 join to form a 5-membered to 10-membered heterocyclic group, which is unsubstituted or 被1至3个取代基取代；以及substituted with 1 to 3 substituents; and (v)n为1。(v) n is 1. 60.如权利要求34所述的化合物，其中该化合物是选自：60. The compound of claim 34, wherein the compound is selected from: [2-吡咯啶-1-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(2，6-二甲基-吗啉-4-基甲基)-7-(2-三氟甲基-苯基)-吡啶并[4，3-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺(顺)；[2-吗啉-4-基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-a]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；[2-(2-吡咯啶-1-基-乙基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；1-吗啉-4-基-3-[4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基]-丙-1-酮；[2-(3-吗啉-4-基-丙基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺盐酸盐；4-三氟甲基苯基-[2-(2，6-二甲基吗啉-4-基甲基)-7-(2-三氟甲基苯基)-喹唑啉-4-基]-胺；[7-(3-甲基-吡啶-2-基)-2-吡咯啶-1-基甲基-吡啶并[3，2-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；(1-{3-[4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基]-丙基}-哌啶-4-基)-甲醇；(2，6-二甲基-吗啉-4-基)-[4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基]-甲酮(顺)；(4-环丙基-苯基)-[2-(2，2-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基]-胺；(4-环丙基-苯基)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基]-胺(顺)；(4-异丙基-苯基)-[2-[(甲基-丙基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基]-胺；(4-异丙基-苯基)-7-(3-三氟甲基-吡啶-2-基)-2-吗啉-4-基甲基-喹唑啉-4-基]-胺；(4-异丙基-苯基)-7-(3-三氟甲基-吡啶-2-基)-2-硫吗啉-4-基甲基-喹唑啉-4-基]-胺；(4-第二-丁基-苯基)-[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-胺(顺)；(4-叔-丁基-苯基)-[2-(1，1-二酮基-1λ6-异噻唑啶-2-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基]-胺；(4-叔-丁基-苯基)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-(2-三氟甲基-苯基)-吡啶并[4，3-d]嘧啶-4-基]-胺(顺)；(4-叔-丁基-苯基)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-胺(顺)；(4-叔-丁基-苯基)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-胺(顺)；(4-叔-丁基-苯基)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-甲基-吡啶-2-基)-喹唑啉-4-基]-胺(顺)；(4-叔-丁基-苯基)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-(6-甲基-吡啶-2-基)-喹唑啉-4-基]-胺(顺)；(4-叔-丁基-苯基)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-吡啶-2-基-喹唑啉-4-基]-胺(顺)；(4-叔-丁基-苯基)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-吡啶-4-基-喹唑啉-4-基]-胺(顺)；(4-叔-丁基-苯基)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-吡啶-3-基-喹唑啉-4-基]-胺(顺)；(4-叔-丁基-苯基)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-吡啶-5-基-喹唑啉-4-基]-胺(顺)；(4-叔-丁基-苯基)-[2-哌啶-1-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；(4-叔-丁基-苯基)-[2-吡咯啶-1-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；(4-叔-丁基-苯基)-[7-(2，4-二甲氧基-嘧啶-5基)-2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-胺(顺)；(4-叔-丁基-苯基)-[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-吡啶并[3，2-d]嘧啶-4-基]-胺(顺)；(4-三氟甲基-苯基)-[7-(3-三氟甲基-吡啶-2-基)-2-(3，3，5-三甲基-一氮庚环-1-基甲基)-喹唑啉-4-基]-胺；(4-三氟甲基-苯基)-[7-(3-三氟甲基-吡啶-2-基)-2-[2-(3，3，5-三甲基-一氮庚环-1-基)-乙基)-喹唑啉-4-基]-胺；(4-三氟甲基-苯基)-{7-(3-三氟甲基-吡啶-2-基)-2-[2-(3，3，5-三甲基-一氮庚环-1-基)-乙基]-喹唑啉-4-基}-胺；(6-叔-丁基-吡啶-3-基)-[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-吡啶并[3，2-d]嘧啶-4-基]-胺(顺)；(6-三氟甲基-吡啶-3-基)-[7-(3-三氟甲基-吡啶-2-基)-2-(3，3，5-三甲基-一氮庚环-1-基甲基)-喹唑啉-4-基]-胺；(R)-(4-异丙基-苯基)-[2-(2-甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；(R)-(4-叔-丁基-苯基)-[2-(2-甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；(R)-(4-叔-丁基-苯基)-[7-(3-氯-吡啶-2-基)-2-(2-甲基-吗啉-4-基甲基)-喹唑啉-4-基]-胺；(R)-[2-(2-甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；(R)-[7-(3-氯-吡啶-2-基)-2-(2-甲基-吗啉-4-基甲基)-喹唑啉-4-基]-(4-异丙基-苯基)-胺；(R)-[7-(3-氯-吡啶-2-基)-2-(2-甲基-吗啉-4-基甲基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；(R，R)-(4-氯-苯基)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；(R，R)-(4-氯-苯基)-[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-胺；(R，R)-(4-乙基-苯基)-[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-胺；(R，R)-(4-氟-苯基)-[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-胺；(R，R)-(4-异丙基-苯基)-[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-胺；(R，R)-(4-叔-丁基-苯基)-[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-胺；(R，R)-(6-叔-丁基-吡啶-3-基)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；(R，R)-(6-叔-丁基-吡啶-3-基)-[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-胺；(R，R)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；(R，R)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡咯-3-基)-胺；(R，R)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-异丙基-苯基)-胺；(R，R)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-乙基-苯基)-胺；(R，R)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-[4-(丙烷-2-磺酰基)-苯基)-胺；(R，R)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；(R，R)-[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；(R，R)-[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；(R，R)-[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-(6-异丙氧基-吡啶-3-基)-胺；(R，R)-[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-[4-(丙烷-2-磺酰基)-苯基]-胺；(R，R)-1-{4-[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基氨基]-苯基}-乙酮；(R，R)-4-[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基氨基]-苄腈；(S)-(4-异丙基-苯基)-[2-(2-甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；(S)-(4-叔-丁基-苯基)-[2-(2-甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；(S)-(4-叔-丁基-苯基)-[7-(3-氯-吡啶-2-基)-2-(2-甲基-吗啉-4-基甲基)-喹唑啉-4-基]-胺；(S)-[2-(1-丙基-吡咯啶-2-基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉4-基]-(4-三氟甲基-苯基)-胺；(S)-[2-(2-甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；(S)-[2-吡咯啶-2-基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；(S)-[7-(3-氯-吡啶-2-基)-2-(2-甲基-吗啉-4-基甲基)-喹唑啉-4-基]-[4-(丙烷-2-磺酰基)-苯基]-胺；(S)-[7-(3-氯-吡啶-2-基)-2-(2-甲基-吗啉-4-基甲基)-喹唑啉-4-基]-(4-异丙基-苯基)-胺；(S，S)-(4-氯-苯基)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；(S，S)-(4-氯-苯基)-[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-胺；(S，S)-(4-叔-丁基-苯基)-[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-胺；(S，S)-(6-叔-丁基-吡啶-3-基)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；(S，S)-(6-叔-丁基-吡啶-3-基)-[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-胺；(S，S)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；(S，S)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡咯-3-基)-胺；(S，S)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-异丙基-苯基)-胺；(S，S)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-乙基-苯基)-胺；(S，S)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-[4-(丙烷-2-磺酰基)-苯基)-胺；(S，S)-[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；(S，S)-[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；(S，S)-[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；(S，S)-[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-[4-(丙烷-2-磺酰基)-苯基]-胺；(S，S)-[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-(4-异丙基-苯基)-胺；(S，S)-[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-(4-乙基-苯基)-胺；[2-(1，1-二酮基-1λ6-[1，2]-噻嗪烷-2-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(1，1-二酮基-1λ6-硫吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(1，4-二噁-8-吖-螺-[4.5]癸-8-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(1，4-二噁-8-吖-螺-[4.5]癸-8-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(1-乙基-哌啶-4-基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(1-甲烷磺酰基-哌啶-4-基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(1-甲基-3，4-二氢-1H-异喹啉-2-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(1-甲基-3，4-二氢-1H-异喹啉-2-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(1-丙基-哌啶-4-基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(1-吡啶-4-基甲基-哌啶-4-基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(2，2-二甲基-吗啉-4-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(2，2-二甲基-吗啉-4-基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；[2-(2，6-二甲基-吗啉-4-基甲基)-7-(2-甲氧基-苯基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺(顺)；[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺(顺)；[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺(顺)；[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺(顺)；[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺(顺)；[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(5-三氟甲基-吡啶-2-基)-胺；[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-[4-(2，2，2-三氟-1-甲基-乙基)苯基]-胺；[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺(顺)；[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(5-三氟甲基-吡啶-2-基)-胺(顺)；[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺(顺)；[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(6-三氟甲基-吡啶-3-基)-胺(顺)；[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲烷磺酰基-苯基)-胺；[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲烷磺酰基-苯基)-胺(顺)；[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(4-甲烷磺酰基-苯基)-胺(顺)；[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(4-三氟甲烷磺酰基-苯基)-胺(顺)；[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-[4-(丙烷-1-磺酰基)-苯基]-胺(顺)；[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-[4-(丙烷-2-磺酰基)-苯基]-胺(顺)；[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(4-异丙基-苯基)-胺(顺)；[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-异丙基-苯基)-胺(顺)；[2-(2，6-二甲基-吗啉-4-基甲基)-7-吡啶-2-基-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺(顺)；[2-(2-乙基-哌啶-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；412[2-(2-乙基-哌啶-1-基乙基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(2-乙基-哌啶-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(2-乙基-哌啶-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(2-甲基-哌啶-1-基乙基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(2-甲基-哌啶-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(2-甲基-哌啶-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(3，3-二甲基-哌啶-1-基乙基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(3，3-二甲基-哌啶-1-基甲基)-7-(3-甲基-吡啶-2-基)-喹唑啉-4-基]-(4-异丙基-苯基)-胺；[2-(3，3-二甲基-哌啶-1-基甲基)-7-(3-甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(3，3-二甲基-哌啶-1-基甲基)-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；[2-(3，3-二甲基-哌啶-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(3，3-二甲基-哌啶-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(3，3-二甲基-哌啶-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(3，3-二甲基-哌啶-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；[2-(3，3-二甲基-哌啶-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；[2-(3，4-二氢-1H-异喹啉-2-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(3，4-二氢-1H-异喹啉-2-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；2-(3，5-二甲基-哌啶-1-基乙基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(3，5-二甲基-哌啶-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(3，5-二甲基-哌啶-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(3，5-二甲基-哌啶-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(3，5-二甲基-哌啶-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺(顺)；[2-(3，5-二甲基-哌啶-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(3-羟基-哌啶-1-基乙基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(3-甲氧基-哌啶-1-基乙基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(3-甲基-哌啶-1-基乙基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(3-甲基-哌啶-1-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(3-甲基-哌啶-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(3-甲基-哌啶-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；[2-(3-吡咯啶-1-基-丙基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(4-环戊基-哌嗪-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(4-乙氧基-哌啶-1-基乙基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(4-乙基-哌嗪-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(4-羟基-哌啶-1-基乙基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(4-异丙基-哌嗪-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(4-甲氧基-哌啶-1-基乙基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(4-甲基-[1，4]二氮庚环-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(4-甲基-哌嗪-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(5-三氟甲基-吡啶-2-基)-胺；[2-(4-甲基-哌嗪-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-[4-(2，2，2-三氟-1-甲基-乙基)-苯基]-胺；[2-(4-甲基-哌嗪-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(4-甲基-哌啶-1-基乙基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(4-甲基-哌啶-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(4-甲基-哌啶-1-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(5，6-二氢-4H-嘧啶-1-基乙基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(5H-四唑-5-基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(6-甲氧基吡啶-3-基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(6-吡咯啶-1-基-吡啶-3-基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(苄基氨基-甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(5-三氟甲基-吡啶-2-基)-胺；[2-(苄基氨基-甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(异丁基氨基-甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(异丙基氨基-甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(八氢-喹啉-1-基乙基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(八氢-喹啉-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(八氢-喹啉-1-基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(叔-丁基氨基-甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[(2-甲氧基-苄基氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(2-甲氧基-乙基氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[(3-甲基-丁基氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[(4-甲氧基-苄基氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(丙烯基-甲基-氨基)-乙基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[(丙烯基-甲基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[(丙烯基-甲基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；[2-[(丙烯基-甲基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(苄基-环丙基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[(苄基-环丙基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(苄基-甲基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(苄基-甲基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[(苄基-甲基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(双-乙氧基甲基-氨基)-甲基]-7-(3-甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[(丁基-乙基-氨基)-乙基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[(丁基-乙基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[(丁基-乙基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(丁基-甲基-氨基)-乙基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[(丁基-甲基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[(丁基-甲基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(环己基-乙基-氨基)-乙基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[(环己基-乙基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[(环己基-乙基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(环己基-甲基-氨基)-乙基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[(环己基-甲基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[(环己基-甲基-氨基)-甲-基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(环丙基甲基-丙基-氨基)-乙基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[(环丙基甲基-丙基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[(环丙基甲基-丙基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(环丙基甲基-丙基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[(环丙基甲基-丙基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[(环丙基甲基-丙基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(乙基-异丙基-氨基)-甲基]-7-(3-甲基-吡啶-2-基)-喹唑啉-4-基]-(4-异丙基-苯基)-胺；[2-[(乙基-异丙基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[(乙基-异丙基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(乙基-丙基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-异丙基-苯基)-胺；[2-[(乙基-丙基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-[4-(吗啉-4-磺酰基)-苯基]-胺；[2-[(己基-甲基-氨基)-乙基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[(己基-甲基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[(己基-甲基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(2，3二氢化茚-1-基-甲基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[(2，3二氢化茚-1-基-甲基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(异丙基-乙基-氨基)-乙基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[(异丙基-甲基-氨基)-乙基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[(异丙基-甲基-氨基)-乙基]-7-(3-甲基-吡啶-2-基)-喹唑啉-4-基]-(4-异丙基-苯基)-胺；[2-[(异丙基-甲基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[(异丙基-甲基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-[4-(吗啉-4-磺酰基)-苯基]-胺；[2-[(异丙基-甲基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(甲基-苯乙基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(甲基-丙基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[(甲基-丙基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-[4-(吗啉-4-磺酰基)-苯基]-胺；[2-[(甲基-丙基-氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[(丙基-甲基-氨基)-乙基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[(四氢-硫吡喃-4-基氨基)-甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[1-(1-甲基-1H-咪唑-2-基甲基)-哌啶-4-基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[2-(1，4-二噁-8-吖-螺[4.5]癸-8-基)-乙基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[2-(1-甲基-3，4-二氢-1H-异喹啉-2-基)-乙基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[2-(2，6-二甲基-吗啉-4-基)-乙基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[2-(3，4-二氢-1H-异喹啉-2-基)-乙基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[2-(4-甲基-哌嗪-1-基)-乙基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[2-(苄基-环丙基-氨基)-乙基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[2-(苄基-甲基-氨基)-乙基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[2-(2，3二氢化茚-1-基-甲基-氨基)-乙基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[2-(甲基-苯乙基-氨基)-乙基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[3-(2，6-二甲基-吗啉-4-基)-丙基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-[3-(2，6-二甲基-吗啉-4-基)-丙基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[3-(2，6-二甲基-吗啉-4-基)-丙基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺(顺)；[2-[3-(3-甲基-哌啶-1-基)-丙基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[3-(4-甲基-哌嗪-1-基)-丙基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[4-(2-二乙基氨基-乙基)-哌嗪-1-基甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[4-(2-二甲基氨基-乙基)-哌嗪-1-基甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[4-(2-甲氧基-乙基)-哌嗪-1-基甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[4-(2-吗啉-4-基-乙基)-哌嗪-1-基甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[4-(2-吡咯啶-1-基-乙基)-哌嗪-1-基甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-[4-(3-二甲基氨基-丙基)-哌嗪-1-基甲基]-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-{[(2-氟-苄基)-甲基-氨基]-甲基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-{[(2-氟-苄基)-甲基-氨基]-甲基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-{[(3-氟-苄基)-甲基-氨基]-甲基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-{[(3-氟-苄基)-甲基-氨基]-甲基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-{[(吡啶-2-基甲基)-氨基]-甲基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-{[双-(2-甲氧基-乙基)-氨基]-甲基}-7-(3-甲基-吡啶-2-基)-喹唑啉-4-基]-(4-异丙基-苯基)-胺；[2-{[双-(2-甲氧基-乙基)-氨基]-甲基}-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；[2-{[双-(2-甲氧基-乙基)-氨基]-甲基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉4-基]-(5-三氟甲基-吡啶-2-基)-胺；[2-{[双-(2-甲氧基-乙基)-氨基]-甲基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-[4-(2，2，2一三氟-1-甲基-乙基)-苯基]-胺；[2-{[双-(2-甲氧基-乙基)-氨基]-甲基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-{[双-(2-甲氧基-乙基)-氨基]-甲基}-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；[2-{[双-(2-甲氧基-乙基)-氨基]-甲基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-{[双-(2-甲氧基-乙基)-氨基]-甲基}-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；[2-{[乙基-(2-甲基-丙烯基)-氨基]-甲基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-{[乙基-(2-甲基-丙烯基)-氨基]-甲基}-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；[2-{[乙基-(2-甲基-丙烯基)-氨基]-甲基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-{[甲基-(1-苯基-乙基)-氨基]-甲基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-{[甲基-(1-苯基-乙基)-氨基]-甲基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-{[甲基-(1-苯基-丙基)-氨基]-甲基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-{[甲基-(1-苯基-丙基)-氨基]-甲基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-{[甲基-(2-甲基-苄基)-氨基]-甲基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-{[甲基-(2-甲基-苄基)-氨基]-甲基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-{[甲基-(2-苯基-乙基)-氨基]-甲基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-{2-[(2-氟-苄基)-甲基-氨基]-乙基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-{2-[(3-氟-苄基)-甲基-氨基]-乙基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉4-基]-(4-三氟甲基-苯基)-胺；[2-{2-[双-(2-甲氧基-乙基)-氨基]-乙基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-{[乙基-(2-甲基-丙烯基)-氨基]-乙基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-{[甲基-(1-苯基-乙基)-氨基]-乙基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-{2-[甲基-(1-苯基-丙基)-氨基]-乙基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-{2-[甲基-(2-甲基-苄基)-氨基]-乙基}-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-一氮庚环-1-基乙基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-一氮庚环-1-基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；[2-一氮庚环-1-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-一氮庚环-1-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-吖丁啶-3-基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；[2-一氮辛环-1-基乙基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-一氮辛环-1-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-一氮辛环-1-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-环己基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-二丙烯基氨基乙基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-二丙烯基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；[2-二丙烯基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-二丙烯基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-二丁基氨基乙基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-二丁基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；[2-二丁基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-二丁基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-二乙基氨基乙基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-二乙基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-二乙基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-二己基氨基乙基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-二己基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-二己基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-二甲基氨基乙基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-二甲基氨基乙基-7-(3-甲基-吡啶-2-基)-喹唑啉-4-基]-(4-异丙基-苯基)-胺；[2-二甲基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-二甲基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-[4-(吗啉-4-磺酰基)-苯基]-胺；[2-二甲基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-二戊基氨基乙基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-二戊基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-二戊基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-二丙基氨基乙基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-二丙基氨基甲基-7-(3-甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-二丙基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；[2-二丙基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-二丙基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-二丙基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；552[2-乙基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-二己基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-咪唑-1-基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；[2-咪唑-1-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-咪唑-1-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-甲基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-吗啉-4-基乙基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-吗啉-4-基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-吗啉-4-基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(6-三氟甲基-吡啶-2-基)-胺；[2-吗啉-4-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(5-三氟甲基-吡啶-2-基)-胺；[2-吗啉-4-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-[4-(2，2，2-三氟-1-甲基-乙基)-苯基]-胺；[2-吗啉-4-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-吗啉-4-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲烷磺酰基-苯基)-胺；[2-吗啉-4-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-辛基氨基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-哌啶-1-基乙基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-哌啶-1-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-[4-(2，2，2-三氟-1-甲基-乙基)-苯基]-胺；[2-哌啶-1-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-哌啶-1-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-哌啶-4-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-哌啶-3-基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-哌啶-4-基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-吡咯啶-1-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-硫吗啉-4-基乙基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-硫吗啉-4-基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；[2-硫吗啉-4-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-硫吗啉-4-基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[7-(3-氯-吡啶-2-基)-2-(2，2-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺(顺)；[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺(顺)；[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺(顺)；[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-(4-三氟甲烷磺酰基-苯基)-胺(顺)；[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-吡啶并[3，2-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺(顺)；[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-吡啶并[3，2-d]嘧啶-4-基]-(6-三氟甲基-吡啶-3-基)-胺(顺)；[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-吡啶并[3，2-d]嘧啶-4-基]-(4-三氟甲烷磺酰基-苯基)-胺(顺)；[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-喹唑啉-4-基]-(4-异丙基-苯基)-胺(顺)；[7-(3-氯-吡啶-2-基)-2-(2，6-二甲基-吗啉-4-基甲基)-吡啶并[3，2-d]嘧啶-4-基]-[4-(吗啉-4-磺酰基)-苯基]-胺；[7-(3-氯-吡啶-2-基)-2-(3，5-二甲基-哌嗪-1-基甲基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺(顺)；[7-(3-氯-吡啶-2-基)-2-咪唑-1-基甲基-吡啶并[3，2-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；{1-[4-(4-叔丁基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基甲基]-吡咯啶-2-基}-甲醇；{1-[4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基甲基]-哌啶-4-基}-甲醇；{1-[4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基甲基]-哌啶-2-基}-甲醇；{1-[4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基甲基]-哌啶-3-基}-甲醇；{1-[7-(3-甲基-吡啶-2-基)-4-(4-三氟甲基-苯基氨基)-骙啉-2-基甲基]-吡咯啶-3-基}-甲醇(对手性)；{1-[7-(3-甲基-吡啶-2-基)-4-(4-三氟甲基-苯基氨基)-骙啉-2-基甲基]-吡咯啶-3-基}-甲醇(对手性)；{1-[7-(3-三氟甲基-吡啶-2-基)-4-(6-三氟甲基-吡啶-3-基氨基)-喹唑啉-2-基甲基]-哌啶-4-基}-甲醇；{1-[7-(3-三氟甲基-吡啶-2-基)-4-(6-三氟甲基-吡啶-3-基氨基)-喹唑啉-2-基甲基]-哌啶-3-基}-甲醇；1-[4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基甲基]-哌啶-4-醇；1-[4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基甲基]-哌啶-3-醇；1-[4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基甲基]-哌啶-4-羧酸酰胺；1-[7-(3-甲基-吡啶-2-基)-4-(4-三氟甲基-苯基-氨基)-喹唑啉-2-基甲基]-吡咯啶-3-醇(对手性)；1-[7-(3-三氟甲基-吡啶-2-基)-4-(6-三氟甲基-吡啶-3-基氨基)-喹唑啉-2-基甲基]-哌啶-4-醇；1-[7-(3-三氟甲基-吡啶-2-基)-4-(6-三氟甲基-吡啶-3-基氨基)-喹唑啉-2-基甲基]-哌啶-3-醇；1-[7-(3-三氟甲基-吡啶-2-基)-4-(6-三氟甲基-吡啶-3-基氨基)-喹唑啉-2-基甲基]-哌啶-4-羧酸酰胺；1-{2-[2-(2，6-二甲基-吗啉-4-基甲基)-4-(4-三氟甲基-苯基氨基)-喹唑啉-7-基]-苯基}-乙酮(顺)；1-{2-[4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基]-乙基}-哌啶-4-羧酸酰胺；1-{3-[4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基]-丙基}-哌啶-4-醇；1-{3-[4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基]-丙基}-哌啶-3-醇；1-{4-[2-(2，6-二甲基-吗啉-4-基甲基)-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基氨基]-苯基}-乙酮(顺)；1-{4-[4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基]-哌啶-1-基}-乙酮；1-{4-[4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基]-哌啶-1-基}-丙-1-酮；1-{4-[7-(3-三氟甲基-吡啶-2-基)-4-(6-三氟甲基-吡啶-3-基氨基)-喹唑啉-2-基甲基]-哌嗪-1-基}-乙酮；1-吡咯啶-1-基-3-[4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基]-丙-1-酮；2-(1-{3-[4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基]-丙基}-哌啶-4-基)-乙醇；2-{[4-(4-叔丁基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基甲基]-丙基-氨基}-乙醇；2-{[4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基甲基]-氨基}-乙醇；2-{1-[4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基甲基]-哌啶-4-基}-乙醇；2-{1-[7-(3-三氟甲基-吡啶-2-基)-4-(6-三氟甲基-吡啶-3-基氨基)-喹唑啉-2-基甲基]-哌啶-4-基}-乙醇；2-{4-[4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-3-基氨基)-喹唑啉-2-基甲基]-哌嗪-1-基}-乙醇；2-{4-[7-(3-三氟甲基-吡啶-2-基)-4-(6-三氟甲基-吡啶-3-基氨基)-喹唑啉-2-基甲基]-哌嗪-1-基}-乙醇；2-甲基-2-{[4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基甲基]-氨基}-丙-1-醇；4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-羧酸二甲基酰胺；4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-羧酸甲基酰胺；4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-羧酸(2-二甲基氨基-乙基)-酰胺；4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-羧酸(2-吗啉-4-基-乙基)-酰胺；4-{2-[4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基]-乙基}-哌嗪-1-甲醛；N，N，N’-三甲基-N’-[4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基甲基]-丙烷-1，3-二胺；以及N-[4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基甲基]-甲烷磺酰胺。[2-Pyrrolidin-1-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)- Amine; [2-(2,6-Dimethyl-morpholin-4-ylmethyl)-7-(2-trifluoromethyl-phenyl)-pyrido[4,3-d]pyrimidine-4 -yl]-(4-trifluoromethyl-phenyl)-amine (cis);[2-morpholin-4-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)- Pyrido[3,2-a]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(2-pyrrolidin-1-yl-ethyl)-7-( 3-Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; 1-morpholin-4-yl-3-[4 -(4-trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-yl]-propan-1-one; [2-( 3-morpholin-4-yl-propyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl) -Amine hydrochloride; 4-trifluoromethylphenyl-[2-(2,6-dimethylmorpholin-4-ylmethyl)-7-(2-trifluoromethylphenyl)-quinone Azolin-4-yl]-amine; [7-(3-methyl-pyridin-2-yl)-2-pyrrolidin-1-ylmethyl-pyrido[3,2-d]pyrimidine-4- base]-(4-trifluoromethyl-phenyl)-amine; (1-{3-[4-(4-trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridine -2-yl)-quinazolin-2-yl]-propyl}-piperidin-4-yl)-methanol; (2,6-dimethyl-morpholin-4-yl)-[4-( 4-trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-yl]-methanone (cis); (4-cyclopropyl -Phenyl)-[2-(2,2-Dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline-2- Base]-amine; (4-cyclopropyl-phenyl)-[2-(2,6-dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridine- 2-yl)-quinazolin-2-yl]-amine (cis); (4-isopropyl-phenyl)-[2-[(methyl-propyl-amino)-methyl]-7- (3-Trifluoromethyl-pyridin-2-yl)-quinazolin-2-yl]-amine; (4-isopropyl-phenyl)-7-(3-trifluoromethyl-pyridine-2 -yl)-2-morpholin-4-ylmethyl-quinazolin-4-yl]-amine; (4-isopropyl-phenyl)-7-(3-trifluoromethyl-pyridine-2 -yl)-2-thiomorpholin-4-ylmethyl-quinazolin-4-yl]-amine; (4-second-butyl-phenyl)-[7-(3-chloro-pyridine- 2-yl)-2-(2,6-dimethyl-morpholin-4-ylmethyl)-quinazolin-4-yl]-amine (cis); (4-tert-butyl-phenyl )-[2-(1,1-diketo-1λ6-isothiazolidin-2-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline-2- Base]-amine; (4-tert-butyl-phenyl)-[2-(2,6-dimethyl-morpholin-4-ylmethyl)-7-(2-trifluoromethyl-benzene Base)-pyrido[4,3-d]pyrimidin-4-yl]-amine (cis); (4-tert-butyl-phenyl)-[2-(2,6-dimethyl-morpholine -4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-amine (cis); (4-tert -Butyl-phenyl)-[2-(2,6-dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[ 3,2-d]pyrimidin-4-yl]-amine (cis); (4-tert-butyl-phenyl)-[2-(2,6-dimethyl-morpholin-4-ylmethyl )-7-(3-methyl-pyridin-2-yl)-quinazolin-4-yl]-amine (cis); (4-tert-butyl-phenyl)-[2-(2,6 -Dimethyl-morpholin-4-ylmethyl)-7-(6-methyl-pyridin-2-yl)-quinazolin-4-yl]-amine (cis); (4-tert-butyl Base-phenyl)-[2-(2,6-dimethyl-morpholin-4-ylmethyl)-7-pyridin-2-yl-quinazolin-4-yl]-amine (cis); (4-tert-butyl-phenyl)-[2-(2,6-dimethyl-morpholin-4-ylmethyl)-7-pyridin-4-yl-quinazolin-4-yl] -amine (cis); (4-tert-butyl-phenyl)-[2-(2,6-dimethyl-morpholin-4-ylmethyl)-7-pyridin-3-yl-quinazole Lin-4-yl]-amine (cis); (4-tert-butyl-phenyl)-[2-(2,6-dimethyl-morpholin-4-ylmethyl)-7-pyridine- 5-yl-quinazolin-4-yl]-amine (cis); (4-tert-butyl-phenyl)-[2-piperidin-1-ylmethyl-7-(3-trifluoromethyl Base-pyridin-2-yl)-quinazolin-4-yl]-amine; (4-tert-butyl-phenyl)-[2-pyrrolidin-1-ylmethyl-7-(3-tri Fluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine; (4-tert-butyl-phenyl)-[7-(2,4-dimethoxy-pyrimidine-5 Base)-2-(2,6-dimethyl-morpholin-4-ylmethyl)-quinazolin-4-yl]-amine (cis); (4-tert-butyl-phenyl)- [7-(3-chloro-pyridin-2-yl)-2-(2,6-dimethyl-morpholin-4-ylmethyl)-pyrido[3,2-d]pyrimidin-4-yl ]-amine (cis); (4-trifluoromethyl-phenyl)-[7-(3-trifluoromethyl-pyridin-2-yl)-2-(3,3,5-trimethyl- Azepan-1-ylmethyl)-quinazolin-4-yl]-amine; (4-trifluoromethyl-phenyl)-[7-(3-trifluoromethyl-pyridine-2- Base)-2-[2-(3,3,5-trimethyl-azepan-1-yl)-ethyl)-quinazolin-4-yl]-amine; (4-trifluoromethane Base-phenyl)-{7-(3-trifluoromethyl-pyridin-2-yl)-2-[2-(3,3,5-trimethyl-azepan-1-yl)- Ethyl]-quinazolin-4-yl}-amine; (6-tert-butyl-pyridin-3-yl)-[7-(3-chloro-pyridin-2-yl)-2-(2, 6-Dimethyl-morpholin-4-ylmethyl)-pyrido[3,2-d]pyrimidin-4-yl]-amine (cis); (6-trifluoromethyl-pyridin-3-yl )-[7-(3-Trifluoromethyl-pyridin-2-yl)-2-(3,3,5-trimethyl-azepan-1-ylmethyl)-quinazoline-4 -yl]-amine; (R)-(4-isopropyl-phenyl)-[2-(2-methyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl- Pyridin-2-yl)-quinazolin-4-yl]-amine; (R)-(4-tert-butyl-phenyl)-[2-(2-methyl-morpholin-4-ylmethyl Base)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine; (R)-(4-tert-butyl-phenyl)-[7- (3-Chloro-pyridin-2-yl)-2-(2-methyl-morpholin-4-ylmethyl)-quinazolin-4-yl]-amine; (R)-[2-(2 -Methyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl )-amine; (R)-[7-(3-chloro-pyridin-2-yl)-2-(2-methyl-morpholin-4-ylmethyl)-quinazolin-4-yl]- (4-isopropyl-phenyl)-amine; (R)-[7-(3-chloro-pyridin-2-yl)-2-(2-methyl-morpholin-4-ylmethyl)- Quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; (R,R)-(4-chloro-phenyl)-[2-(2,6-dimethyl- Morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine; (R,R)-(4-chloro-benzene Base)-[7-(3-chloro-pyridin-2-yl)-2-(2,6-dimethyl-morpholin-4-ylmethyl)-quinazolin-4-yl]-amine; (R, R)-(4-ethyl-phenyl)-[7-(3-chloro-pyridin-2-yl)-2-(2,6-dimethyl-morpholin-4-ylmethyl )-quinazolin-4-yl]-amine; (R, R)-(4-fluoro-phenyl)-[7-(3-chloro-pyridin-2-yl)-2-(2,6- Dimethyl-morpholin-4-ylmethyl)-quinazolin-4-yl]-amine; (R,R)-(4-isopropyl-phenyl)-[7-(3-chloro- Pyridin-2-yl)-2-(2,6-dimethyl-morpholin-4-ylmethyl)-quinazolin-4-yl]-amine; (R,R)-(4-tert- Butyl-phenyl)-[7-(3-chloro-pyridin-2-yl)-2-(2,6-dimethyl-morpholin-4-ylmethyl)-quinazolin-4-yl ]-amine; (R, R)-(6-tert-butyl-pyridin-3-yl)-[2-(2,6-dimethyl-morpholin-4-ylmethyl)-7-( 3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine; (R, R)-(6-tert-butyl-pyridin-3-yl)-[7-( 3-chloro-pyridin-2-yl)-2-(2,6-dimethyl-morpholin-4-ylmethyl)-quinazolin-4-yl]-amine; (R,R)-[ 2-(2,6-Dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4- Trifluoromethyl-phenyl)-amine; (R,R)-[2-(2,6-Dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridine -2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyrrol-3-yl)-amine; (R,R)-[2-(2,6-dimethyl- Morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-isopropyl-phenyl)-amine; ( R, R)-[2-(2,6-Dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline-4- base]-(4-ethyl-phenyl)-amine; (R,R)-[2-(2,6-dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoro Methyl-pyridin-2-yl)-quinazolin-4-yl]-[4-(propane-2-sulfonyl)-phenyl)-amine; (R,R)-[2-(2,6 -Dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-yl]-(4 -trifluoromethyl-phenyl)-amine; (R,R)-[7-(3-chloro-pyridin-2-yl)-2-(2,6-dimethyl-morpholin-4-yl Methyl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; (R,R)-[7-(3-chloro-pyridin-2-yl)-2- (2,6-Dimethyl-morpholin-4-ylmethyl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; (R, R) -[7-(3-Chloro-pyridin-2-yl)-2-(2,6-dimethyl-morpholin-4-ylmethyl)-quinazolin-4-yl]-(6-iso Propoxy-pyridin-3-yl)-amine; (R,R)-[7-(3-chloro-pyridin-2-yl)-2-(2,6-dimethyl-morpholine-4- (R,R)-1-{4-[7-(3-chloro -pyridin-2-yl)-2-(2,6-dimethyl-morpholin-4-ylmethyl)-quinazolin-4-ylamino]-phenyl}-ethanone; (R,R )-4-[7-(3-chloro-pyridin-2-yl)-2-(2,6-dimethyl-morpholin-4-ylmethyl)-quinazolin-4-ylamino]- Benzonitrile; (S)-(4-isopropyl-phenyl)-[2-(2-methyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridine-2 -yl)-quinazolin-4-yl]-amine; (S)-(4-tert-butyl-phenyl)-[2-(2-methyl-morpholin-4-ylmethyl)- 7-(3-Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine; (S)-(4-tert-butyl-phenyl)-[7-(3- Chloro-pyridin-2-yl)-2-(2-methyl-morpholin-4-ylmethyl)-quinazolin-4-yl]-amine; (S)-[2-(1-propyl -pyrrolidin-2-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin 4-yl]-(4-trifluoromethyl-phenyl)-amine; (S )-[2-(2-Methyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4- Trifluoromethyl-phenyl)-amine; (S)-[2-pyrrolidin-2-yl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl] -(4-Trifluoromethyl-phenyl)-amine; (S)-[7-(3-chloro-pyridin-2-yl)-2-(2-methyl-morpholin-4-ylmethyl )-quinazolin-4-yl]-[4-(propane-2-sulfonyl)-phenyl]-amine; (S)-[7-(3-chloro-pyridin-2-yl)-2- (2-Methyl-morpholin-4-ylmethyl)-quinazolin-4-yl]-(4-isopropyl-phenyl)-amine; (S,S)-(4-chloro-benzene base)-[2-(2,6-dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl] -amine; (S,S)-(4-chloro-phenyl)-[7-(3-chloro-pyridin-2-yl)-2-(2,6-dimethyl-morpholin-4-yl Methyl)-quinazolin-4-yl]-amine; (S,S)-(4-tert-butyl-phenyl)-[7-(3-chloro-pyridin-2-yl)-2- (2,6-Dimethyl-morpholin-4-ylmethyl)-quinazolin-4-yl]-amine; (S,S)-(6-tert-butyl-pyridin-3-yl) -[2-(2,6-Dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine ; (S, S)-(6-tert-butyl-pyridin-3-yl)-[7-(3-chloro-pyridin-2-yl)-2-(2,6-dimethyl-morpholine -4-ylmethyl)-quinazolin-4-yl]-amine; (S, S)-[2-(2,6-dimethyl-morpholin-4-ylmethyl)-7-( 3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; (S,S)-[2-(2,6 -Dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyrrole -3-yl)-amine; (S,S)-[2-(2,6-Dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridine-2- base)-quinazolin-4-yl]-(4-isopropyl-phenyl)-amine; (S,S)-[2-(2,6-dimethyl-morpholin-4-ylmethyl Base)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-ethyl-phenyl)-amine; (S,S)-[2- (2,6-Dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-[4-(propane -2-sulfonyl)-phenyl)-amine; (S,S)-[2-(2,6-dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl -pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine; (S,S)-[7-(3- Chloro-pyridin-2-yl)-2-(2,6-dimethyl-morpholin-4-ylmethyl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl) -amine; (S,S)-[7-(3-chloro-pyridin-2-yl)-2-(2,6-dimethyl-morpholin-4-ylmethyl)-quinazoline-4 -yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; (S,S)-[7-(3-chloro-pyridin-2-yl)-2-(2,6-di Methyl-morpholin-4-ylmethyl)-quinazolin-4-yl]-[4-(propane-2-sulfonyl)-phenyl]-amine; (S, S)-[7-( 3-chloro-pyridin-2-yl)-2-(2,6-dimethyl-morpholin-4-ylmethyl)-quinazolin-4-yl]-(4-isopropyl-phenyl )-amine; (S, S)-[7-(3-chloro-pyridin-2-yl)-2-(2,6-dimethyl-morpholin-4-ylmethyl)-quinazoline- 4-yl]-(4-ethyl-phenyl)-amine; [2-(1,1-diketonyl-1λ6-[1,2]-thiazinane-2-ylmethyl)-7- (3-Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(1,1-diketonyl- 1λ6-thiomorpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridine-3 -yl)-amine; [2-(1,4-Dioxa-8-acridine-spiro-[4.5]dec-8-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl )-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(1,4-dioxa-8-acridine-spiro-[4.5]dec-8-yl Methyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2- (1-Ethyl-piperidin-4-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl )-amine; [2-(1-methanesulfonyl-piperidin-4-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4 -trifluoromethyl-phenyl)-amine; [2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-7-(3-trifluoromethyl -pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(1-methyl-3,4-dihydro-1H-iso Quinolin-2-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl) -amine; [2-(1-propyl-piperidin-4-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-tri Fluoromethyl-phenyl)-amine; [2-(1-pyridin-4-ylmethyl-piperidin-4-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinone Azolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(2,2-dimethyl-morpholin-4-ylmethyl-7-(3-trifluoro Methyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(2,2-dimethyl-morpholine-4- Methyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine ; [2-(2,6-Dimethyl-morpholin-4-ylmethyl)-7-(2-methoxy-phenyl)-quinazolin-4-yl]-(4-trifluoro Methyl-phenyl)-amine (cis); [2-(2,6-Dimethyl-morpholin-4-ylmethyl)-7-(3-methyl-pyridin-2-yl)-pyridine And[3,2-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine (cis);[2-(2,6-dimethyl-morpholin-4-yl Methyl)-7-(3-methyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine (cis); [2-(2 , 6-Dimethyl-morpholin-4-ylmethyl)-7-(3-methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-(4 -Trifluoromethyl-phenyl)-amine (cis); [2-(2,6-Dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridine-2 -yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-(2,6-dimethyl-morpholin-4-ylmethyl) -7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(2,6-di Methyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl) -amine (cis); [2-(2,6-dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline-4 -yl]-(5-trifluoromethyl-pyridin-2-yl)-amine; [2-(2,6-dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoro Methyl-pyridin-2-yl)-quinazolin-4-yl]-[4-(2,2,2-trifluoro-1-methyl-ethyl)phenyl]-amine; [2-( 2,6-Dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl Base-pyridin-3-yl)-amine (cis); [2-(2,6-Dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridine-2- Base)-quinazolin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine (cis); [2-(2,6-dimethyl-morpholin-4-yl Methyl)-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine (cis); [2-(2,6-Dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2- d] pyrimidin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine (cis); [2-(2,6-dimethyl-morpholin-4-ylmethyl) -7-(3-Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine; [2-(2,6- Dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethanesulfonyl-benzene Base)-amine (cis); [2-(2,6-Dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[ 3,2-d]pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amine (cis);[2-(2,6-dimethyl-morpholin-4-ylmethyl) -7-(3-Trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine (cis ); [2-(2,6-Dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d] Pyrimidin-4-yl]-[4-(propane-1-sulfonyl)-phenyl]-amine (cis);[2-(2,6-dimethyl-morpholin-4-ylmethyl)- 7-(3-Trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-yl]-[4-(propane-2-sulfonyl)-phenyl]-amine (cis); [2-(2,6-Dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2- d] pyrimidin-4-yl]-(4-isopropyl-phenyl)-amine (cis); [2-(2,6-dimethyl-morpholin-4-ylmethyl)-7-( 3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-isopropyl-phenyl)-amine (cis); [2-(2,6-dimethyl -morpholin-4-ylmethyl)-7-pyridin-2-yl-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine (cis); [2-(2 -Ethyl-piperidin-1-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl )-amine; 412[2-(2-Ethyl-piperidin-1-ylethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]- (4-Trifluoromethyl-phenyl)-amine; [2-(2-Ethyl-piperidin-1-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)- Quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(2-Ethyl-piperidin-1-ylmethyl)-7-(3-trifluoromethyl Base-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-(2-methyl-piperidin-1-yl Ethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(2- Methyl-piperidin-1-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl) -amine; [2-(2-methyl-piperidin-1-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6 -Trifluoromethyl-pyridin-3-yl)-amine; [2-(3,3-Dimethyl-piperidin-1-ylethyl)-7-(3-trifluoromethyl-pyridine-2 -yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(3,3-dimethyl-piperidin-1-ylmethyl)-7 -(3-Methyl-pyridin-2-yl)-quinazolin-4-yl]-(4-isopropyl-phenyl)-amine; [2-(3,3-Dimethyl-piperidine -1-ylmethyl)-7-(3-methyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-( 3,3-Dimethyl-piperidin-1-ylmethyl)-7-(3-methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-( 4-Trifluoromethyl-phenyl)-amine; [2-(3,3-Dimethyl-piperidin-1-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl )-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(3,3-dimethyl-piperidin-1-ylmethyl)-7-( 3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-(3,3-dimethyl Base-piperidin-1-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)- Amine; [2-(3,3-Dimethyl-piperidin-1-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d] Pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(3,3-dimethyl-piperidin-1-ylmethyl)-7-(3-trifluoro Methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(3,4-dihydro -1H-isoquinolin-2-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl )-amine; [2-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline-4 -yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; 2-(3,5-dimethyl-piperidin-1-ylethyl)-7-(3-trifluoromethyl Base-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(3,5-dimethyl-piperidin-1-yl Methyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(3, 5-Dimethyl-piperidin-1-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl- Pyridin-3-yl)-amine; [2-(3,5-Dimethyl-piperidin-1-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazole Phenyl-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(3,5-dimethyl-piperidin-1-ylmethyl)-7-(3-trifluoro Methyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine (cis); [2-(3,5 -Dimethyl-piperidin-1-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridine -3-yl)-amine; [2-(3-hydroxy-piperidin-1-ylethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl ]-(4-trifluoromethyl-phenyl)-amine; [2-(3-methoxy-piperidin-1-ylethyl)-7-(3-trifluoromethyl-pyridine-2- Base)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(3-methyl-piperidin-1-ylethyl)-7-(3- Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(3-methyl-piperidin-1-yl Methyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-( 3-Methyl-piperidin-1-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-benzene base)-amine; [2-(3-methyl-piperidin-1-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d] Pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(3-pyrrolidin-1-yl-propyl)-7-(3-trifluoromethyl-pyridine- 2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(4-cyclopentyl-piperazin-1-ylmethyl)-7- (3-Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(4-ethoxy-piperidine -1-ylethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2 -(4-Ethyl-piperazin-1-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl -phenyl)-amine; [2-(4-hydroxy-piperidin-1-ylethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl] -(4-Trifluoromethyl-phenyl)-amine; [2-(4-Isopropyl-piperazin-1-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl )-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(4-methoxy-piperidin-1-ylethyl)-7-(3- Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(4-methyl-[1,4]di Azepan-1-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine ; [2-(4-Methyl-piperazin-1-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(5-tri Fluoromethyl-pyridin-2-yl)-amine; [2-(4-methyl-piperazin-1-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinone Azolin-4-yl]-[4-(2,2,2-trifluoro-1-methyl-ethyl)-phenyl]-amine; [2-(4-methyl-piperazine-1- Methyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(4 -Methyl-piperidin-1-ylethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl )-amine; [2-(4-methyl-piperidin-1-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-( 4-trifluoromethyl-phenyl)-amine; [2-(4-methyl-piperidin-1-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazole Phenyl-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-(5,6-dihydro-4H-pyrimidin-1-ylethyl)-7-(3 -Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(5H-tetrazol-5-yl)- 7-(3-Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(6-Methoxypyridine -3-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-( 6-pyrrolidin-1-yl-pyridin-3-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl- phenyl)-amine; [2-(benzylamino-methyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(5-trifluoromethyl Base-pyridin-2-yl)-amine; [2-(Benzylamino-methyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-( 6-trifluoromethyl-pyridin-3-yl)-amine; [2-(isobutylamino-methyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline- 4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(isopropylamino-methyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinone Azolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(octahydro-quinolin-1-ylethyl)-7-(3-trifluoromethyl-pyridine -2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(octahydro-quinolin-1-ylmethyl)-7-(3 -trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(octahydro-quinolin-1-ylmethyl Base) -7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-( tert-Butylamino-methyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-[(2-Methoxy-benzylamino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-tri Fluoromethyl-pyridin-3-yl)-amine; [2-[(2-Methoxy-ethylamino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)- Quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-[(3-methyl-butylamino)-methyl]-7-(3-trifluoromethyl Base-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-[(4-methoxy-benzylamino)-methyl ]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-[( Propyl-methyl-amino)-ethyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl) -amine; [2-[(propenyl-methyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4- Trifluoromethyl-phenyl)-amine; [2-[(propenyl-methyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3 , 2-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-[(propenyl-methyl-amino)-methyl]-7-(3-tri Fluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-[(benzyl Base-cyclopropyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl) -amine; [2-[(benzyl-cyclopropyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6 -trifluoromethyl-pyridin-3-yl)-amine; [2-[(benzyl-methyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)- Quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-[(benzyl-methyl-amino)-methyl]-7-(3-tri Fluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-[(benzyl-methyl-amino)-methyl ]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-[( Bis-ethoxymethyl-amino)-methyl]-7-(3-methyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl) -amine; [2-[(butyl-ethyl-amino)-ethyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4- Trifluoromethyl-phenyl)-amine; [2-[(Butyl-ethyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline- 4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-[(butyl-ethyl-amino)-methyl]-7-(3-trifluoromethyl-pyridine-2 -yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-[(butyl-methyl-amino)-ethyl]-7- (3-Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-[(butyl-methyl-amino )-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-[ (Butyl-methyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridine- 3-yl)-amine; [2-[(cyclohexyl-ethyl-amino)-ethyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl] -(4-Trifluoromethyl-phenyl)-amine; [2-[(cyclohexyl-ethyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)- Quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-[(cyclohexyl-ethyl-amino)-methyl]-7-(3-trifluoromethyl -pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-[(cyclohexyl-methyl-amino)-ethyl ]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-[(cyclohexyl- Methyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-[(cyclohexyl-methyl-amino)-methyl-yl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoro Methyl-pyridin-3-yl)-amine; [2-[(cyclopropylmethyl-propyl-amino)-ethyl]-7-(3-trifluoromethyl-pyridin-2-yl)- Quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-[(cyclopropylmethyl-propyl-amino)-methyl]-7-(3-tri Fluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-[(cyclopropylmethyl-propyl-amino) -Methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2 -[(cyclopropylmethyl-propyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoro Methyl-phenyl)-amine; [2-[(cyclopropylmethyl-propyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline -4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-[(cyclopropylmethyl-propyl-amino)-methyl]-7-(3-trifluoromethyl -pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-[(ethyl-isopropyl-amino)-methanol Base]-7-(3-methyl-pyridin-2-yl)-quinazolin-4-yl]-(4-isopropyl-phenyl)-amine; [2-[(ethyl-isopropyl Base-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [ 2-[(Ethyl-isopropyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl Base-pyridin-3-yl)-amine; [2-[(Ethyl-propyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline- 4-yl]-(4-isopropyl-phenyl)-amine; [2-[(ethyl-propyl-amino)-methyl]-7-(3-trifluoromethyl-pyridine-2- Base)-quinazolin-4-yl]-[4-(morpholine-4-sulfonyl)-phenyl]-amine; [2-[(hexyl-methyl-amino)-ethyl]-7- (3-Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-[(hexyl-methyl-amino) -Methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-[( Hexyl-methyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridine-3- base)-amine; [2-[(2,3-indan-1-yl-methyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazole Lin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-[(2,3 indan-1-yl-methyl-amino)-methyl]-7-( 3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-[(isopropyl-ethyl -amino)-ethyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [ 2-[(isopropyl-methyl-amino)-ethyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl Base-phenyl)-amine; [2-[(isopropyl-methyl-amino)-ethyl]-7-(3-methyl-pyridin-2-yl)-quinazolin-4-yl] -(4-Isopropyl-phenyl)-amine; [2-[(isopropyl-methyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)- Quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-[(isopropyl-methyl-amino)-methyl]-7-(3-trifluoromethyl Base-pyridin-2-yl)-quinazolin-4-yl]-[4-(morpholine-4-sulfonyl)-phenyl]-amine; [2-[(isopropyl-methyl-amino )-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [ 2-[(Methyl-phenethyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl Base-pyridin-3-yl)-amine; [2-[(Methyl-propyl-amino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline- 4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-[(methyl-propyl-amino)-methyl]-7-(3-trifluoromethyl-pyridine-2 -yl)-quinazolin-4-yl]-[4-(morpholine-4-sulfonyl)-phenyl]-amine; [2-[(methyl-propyl-amino)-methyl]- 7-(3-Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-[(propyl -Methyl-amino)-ethyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine ; [2-[(tetrahydro-thiopyran-4-ylamino)-methyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-( 6-trifluoromethyl-pyridin-3-yl)-amine; [2-[1-(1-methyl-1H-imidazol-2-ylmethyl)-piperidin-4-yl]-7-( 3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-[2-(1,4-diox -8-acridine-spiro[4.5]dec-8-yl)-ethyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-tri Fluoromethyl-phenyl)-amine; [2-[2-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-7-(3-tri Fluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-[2-(2,6-dimethyl-morph Lin-4-yl)-ethyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine ; [2-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-ethyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline -4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-[2-(4-methyl-piperazin-1-yl)-ethyl]-7-(3-tri Fluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-[2-(benzyl-cyclopropyl-amino) -Ethyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-[2 -(Benzyl-methyl-amino)-ethyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-benzene Base)-amine; [2-[2-(2,3 indan-1-yl-methyl-amino)-ethyl]-7-(3-trifluoromethyl-pyridin-2-yl)- Quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-[2-(methyl-phenethyl-amino)-ethyl]-7-(3-tri Fluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-[3-(2,6-dimethyl-morph Lin-4-yl)-propyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl )-amine; [2-[3-(2,6-Dimethyl-morpholin-4-yl)-propyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazole [2-[3-(2,6-Dimethyl-morpholin-4-yl)-propyl]-7- (3-Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine (cis); [2-[3-(3- Methyl-piperidin-1-yl)-propyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-benzene Base)-amine; [2-[3-(4-Methyl-piperazin-1-yl)-propyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline- 4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-[4-(2-diethylamino-ethyl)-piperazin-1-ylmethyl]-7-( 3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-[4-(2-dimethylamino -Ethyl)-piperazin-1-ylmethyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-benzene base)-amine; [2-[4-(2-methoxy-ethyl)-piperazin-1-ylmethyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinone Azolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-[4-(2-morpholin-4-yl-ethyl)-piperazin-1-ylmethyl ]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-[4-(2 -pyrrolidin-1-yl-ethyl)-piperazin-1-ylmethyl]-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4 -Trifluoromethyl-phenyl)-amine; [2-[4-(3-Dimethylamino-propyl)-piperazin-1-ylmethyl]-7-(3-trifluoromethyl- Pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-{[(2-fluoro-benzyl)-methyl-amino]- Methyl}-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-{[( 2-Fluoro-benzyl)-methyl-amino]-methyl}-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl Base-pyridin-3-yl)-amine; [2-{[(3-fluoro-benzyl)-methyl-amino]-methyl}-7-(3-trifluoromethyl-pyridin-2-yl )-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-{[(3-fluoro-benzyl)-methyl-amino]-methyl}-7 -(3-Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-{[(pyridine- 2-ylmethyl)-amino]-methyl}-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridine- 3-yl)-amine; [2-{[bis-(2-methoxy-ethyl)-amino]-methyl}-7-(3-methyl-pyridin-2-yl)-quinazoline -4-yl]-(4-isopropyl-phenyl)-amine; [2-{[bis-(2-methoxy-ethyl)-amino]-methyl}-7-(3-methyl Base-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-{[bis-(2-methyl Oxygen-ethyl)-amino]-methyl}-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin4-yl]-(5-trifluoromethyl-pyridine-2 -yl)-amine; [2-{[bis-(2-methoxy-ethyl)-amino]-methyl}-7-(3-trifluoromethyl-pyridin-2-yl)-quinazole Phenyl-4-yl]-[4-(2,2,2-trifluoro-1-methyl-ethyl)-phenyl]-amine; [2-{[bis-(2-methoxy-ethyl) Base)-amino]-methyl}-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-{[bis-(2-methoxy-ethyl)-amino]-methyl}-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d ]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-{[bis-(2-methoxy-ethyl)-amino]-methyl}-7-( 3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-{[bis-(2- Methoxy-ethyl)-amino]-methyl}-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-(4 -trifluoromethyl-phenyl)-amine; [2-{[ethyl-(2-methyl-propenyl)-amino]-methyl}-7-(3-trifluoromethyl-pyridine-2 -yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-{[ethyl-(2-methyl-propenyl)-amino]-methyl }-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [ 2-{[Ethyl-(2-methyl-propenyl)-amino]-methyl}-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]- (6-Trifluoromethyl-pyridin-3-yl)-amine; [2-{[methyl-(1-phenyl-ethyl)-amino]-methyl}-7-(3-trifluoromethyl Base-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-{[methyl-(1-phenyl-ethyl)- Amino]-methyl}-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-{[Methyl-(1-phenyl-propyl)-amino]-methyl}-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl] -(4-Trifluoromethyl-phenyl)-amine; [2-{[methyl-(1-phenyl-propyl)-amino]-methyl}-7-(3-trifluoromethyl- Pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-{[methyl-(2-methyl-benzyl) -amino]-methyl}-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2 -{[Methyl-(2-methyl-benzyl)-amino]-methyl}-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-( 6-trifluoromethyl-pyridin-3-yl)-amine; [2-{[methyl-(2-phenyl-ethyl)-amino]-methyl}-7-(3-trifluoromethyl -pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-{2-[(2-fluoro-benzyl)-methyl- Amino]-ethyl}-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2- {2-[(3-fluoro-benzyl)-methyl-amino]-ethyl}-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin 4-yl]-(4 -trifluoromethyl-phenyl)-amine; [2-{2-[bis-(2-methoxy-ethyl)-amino]-ethyl}-7-(3-trifluoromethyl-pyridine -2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-{[ethyl-(2-methyl-propenyl)-amino]- Ethyl}-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-{[form Base-(1-phenyl-ethyl)-amino]-ethyl}-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoro Methyl-phenyl)-amine; [2-{2-[Methyl-(1-phenyl-propyl)-amino]-ethyl}-7-(3-trifluoromethyl-pyridine-2- Base)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-{2-[methyl-(2-methyl-benzyl)-amino]-ethyl Base}-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-azepan -1-ylethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2- Azepan-1-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-yl]-(4-trifluoromethyl Base-phenyl)-amine; [2-Azepan-1-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4 -Trifluoromethyl-phenyl)-amine; [2-Azepan-1-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl ]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-azetidin-3-yl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[ 2,3-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-azacycline-1-ylethyl-7-(3-trifluoromethyl -pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-azacycline-1-ylmethyl-7-(3- Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-azacycline-1-ylmethyl-7 -(3-Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-cyclohexylaminomethyl -7-(3-Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-Dipropenylaminoethyl -7-(3-Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-Dipropenylaminomethyl -7-(3-Trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2 - Dipropenylaminomethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2 -Dipropenylaminomethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine ;[2-Dibutylaminoethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine ; [2-Dibutylaminomethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-yl]-(4-trifluoromethyl Base-phenyl)-amine; [2-Dibutylaminomethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl Base-phenyl)-amine; [2-Dibutylaminomethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl Base-pyridin-3-yl)-amine; [2-Diethylaminoethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4- Trifluoromethyl-phenyl)-amine; [2-Diethylaminomethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4- Trifluoromethyl-phenyl)-amine; [2-diethylaminomethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6- Trifluoromethyl-pyridin-3-yl)-amine; [2-Dihexylaminoethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-( 4-trifluoromethyl-phenyl)-amine; [2-dihexylaminomethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4 -trifluoromethyl-phenyl)-amine; [2-dihexylaminomethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6- Trifluoromethyl-pyridin-3-yl)-amine; [2-Dimethylaminoethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]- (4-trifluoromethyl-phenyl)-amine; [2-dimethylaminoethyl-7-(3-methyl-pyridin-2-yl)-quinazolin-4-yl]-(4 -isopropyl-phenyl)-amine; [2-Dimethylaminomethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4- Trifluoromethyl-phenyl)-amine; [2-Dimethylaminomethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-[4- (Morpholine-4-sulfonyl)-phenyl]-amine; [2-Dimethylaminomethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl ]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-dipentylaminoethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline- 4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-dipentylaminomethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline- 4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-dipentylaminomethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline- 4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-dipropylaminoethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinone Azolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-dipropylaminomethyl-7-(3-methyl-pyridin-2-yl)-quinazoline -4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-dipropylaminomethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[ 3,2-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-dipropylaminomethyl-7-(3-trifluoromethyl-pyridine-2 -yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-dipropylaminomethyl-7-(3-trifluoromethyl- Pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-dipropylaminomethyl-7-(3-trifluoromethyl- Pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; 552[2-ethylaminomethyl-7-(3-trifluoro Methyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-dihexylaminomethyl-7-(3-trifluoromethyl Base-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-imidazol-1-ylmethyl-7-(3-trifluoro Methyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-imidazol-1-ylmethyl -7-(3-Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-imidazole-1 -ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-methyl Aminomethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-morpholine- 4-ylethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-morphol Lin-4-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-yl]-(6-trifluoromethyl-pyridine -3-yl)-amine; [2-morpholin-4-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidine-4- Base]-(6-trifluoromethyl-pyridin-2-yl)-amine; [2-morpholin-4-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinone Azolin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine; [2-morpholin-4-ylmethyl-7-(3-trifluoromethyl-pyridin-2 -yl)-quinazolin-4-yl]-[4-(2,2,2-trifluoro-1-methyl-ethyl)-phenyl]-amine; [2-morpholin-4-yl Methyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-morpho Lin-4-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine; [ 2-Morpholin-4-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine ; [2-octylaminomethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-Piperidin-1-ylethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)- Amine; [2-piperidin-1-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-[4-(2,2,2- Trifluoro-1-methyl-ethyl)-phenyl]-amine; [2-piperidin-1-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline -4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-piperidin-1-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinone Azolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-piperidin-4-ylmethyl-7-(3-trifluoromethyl-pyridin-2 -yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-piperidin-3-yl-7-(3-trifluoromethyl-pyridine-2 -yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-piperidin-4-yl-7-(3-trifluoromethyl-pyridine-2 -yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-pyrrolidin-1-ylmethyl-7-(3-trifluoromethyl-pyridine -2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-thiomorpholin-4-ylethyl-7-(3- Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-thiomorpholin-4-ylmethyl-7- (3-Trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-thiomorph Lin-4-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine ; [2-thiomorpholin-4-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl )-amine; [7-(3-chloro-pyridin-2-yl)-2-(2,2-dimethyl-morpholin-4-ylmethyl)-quinazolin-4-yl]-( 4-trifluoromethyl-phenyl)-amine (cis); [7-(3-chloro-pyridin-2-yl)-2-(2,6-dimethyl-morpholin-4-ylmethyl )-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine (cis); [7-(3-chloro-pyridin-2-yl)-2-(2,6- Dimethyl-morpholin-4-ylmethyl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine (cis); [7-(3-chloro -pyridin-2-yl)-2-(2,6-dimethyl-morpholin-4-ylmethyl)-quinazolin-4-yl]-(4-trifluoromethanesulfonyl-phenyl) -amine (cis); [7-(3-chloro-pyridin-2-yl)-2-(2,6-dimethyl-morpholin-4-ylmethyl)-pyrido[3,2-d ]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine (cis);[7-(3-chloro-pyridin-2-yl)-2-(2,6-dimethyl -morpholin-4-ylmethyl)-pyrido[3,2-d]pyrimidin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine (cis); [7- (3-chloro-pyridin-2-yl)-2-(2,6-dimethyl-morpholin-4-ylmethyl)-pyrido[3,2-d]pyrimidin-4-yl]-( 4-Trifluoromethanesulfonyl-phenyl)-amine (cis); [7-(3-chloro-pyridin-2-yl)-2-(2,6-dimethyl-morpholin-4-ylmethyl Base)-quinazolin-4-yl]-(4-isopropyl-phenyl)-amine (cis); [7-(3-chloro-pyridin-2-yl)-2-(2,6- Dimethyl-morpholin-4-ylmethyl)-pyrido[3,2-d]pyrimidin-4-yl]-[4-(morpholin-4-sulfonyl)-phenyl]-amine; [ 7-(3-chloro-pyridin-2-yl)-2-(3,5-dimethyl-piperazin-1-ylmethyl)-quinazolin-4-yl]-(4-trifluoromethyl Base-phenyl)-amine (cis); [7-(3-chloro-pyridin-2-yl)-2-imidazol-1-ylmethyl-pyrido[3,2-d]pyrimidin-4-yl ]-(4-trifluoromethyl-phenyl)-amine; {1-[4-(4-tert-butyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl) -quinazolin-2-ylmethyl]-pyrrolidin-2-yl}-methanol; {1-[4-(4-trifluoromethyl-phenylamino)-7-(3-trifluoromethyl -pyridin-2-yl)-quinazolin-2-ylmethyl]-piperidin-4-yl}-methanol; {1-[4-(4-trifluoromethyl-phenylamino)-7- (3-Trifluoromethyl-pyridin-2-yl)-quinazolin-2-ylmethyl]-piperidin-2-yl}-methanol; {1-[4-(4-trifluoromethyl- Phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-ylmethyl]-piperidin-3-yl}-methanol; {1-[7-( 3-Methyl-pyridin-2-yl)-4-(4-trifluoromethyl-phenylamino)-linolin-2-ylmethyl]-pyrrolidin-3-yl}-methanol (chiral) ; {1-[7-(3-Methyl-pyridin-2-yl)-4-(4-trifluoromethyl-phenylamino)-lin-2-ylmethyl]-pyrrolidin-3- Base}-methanol (chiral); {1-[7-(3-trifluoromethyl-pyridin-2-yl)-4-(6-trifluoromethyl-pyridin-3-ylamino)-quinazole Lin-2-ylmethyl]-piperidin-4-yl}-methanol; {1-[7-(3-trifluoromethyl-pyridin-2-yl)-4-(6-trifluoromethyl- Pyridin-3-ylamino)-quinazolin-2-ylmethyl]-piperidin-3-yl}-methanol; 1-[4-(4-trifluoromethyl-phenylamino)-7-( 3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-ylmethyl]-piperidin-4-ol; 1-[4-(4-trifluoromethyl-phenylamino)- 7-(3-Trifluoromethyl-pyridin-2-yl)-quinazolin-2-ylmethyl]-piperidin-3-ol; 1-[4-(4-Trifluoromethyl-phenyl Amino)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-ylmethyl]-piperidine-4-carboxylic acid amide; 1-[7-(3-methyl -pyridin-2-yl)-4-(4-trifluoromethyl-phenyl-amino)-quinazolin-2-ylmethyl]-pyrrolidin-3-ol (chiral); 1-[7 -(3-Trifluoromethyl-pyridin-2-yl)-4-(6-trifluoromethyl-pyridin-3-ylamino)-quinazolin-2-ylmethyl]-piperidine-4- Alcohol; 1-[7-(3-trifluoromethyl-pyridin-2-yl)-4-(6-trifluoromethyl-pyridin-3-ylamino)-quinazolin-2-ylmethyl] -Piperidin-3-ol; 1-[7-(3-trifluoromethyl-pyridin-2-yl)-4-(6-trifluoromethyl-pyridin-3-ylamino)-quinazoline- 2-ylmethyl]-piperidine-4-carboxylic acid amide; 1-{2-[2-(2,6-dimethyl-morpholin-4-ylmethyl)-4-(4-trifluoro Methyl-phenylamino)-quinazolin-7-yl]-phenyl}-ethanone (cis); 1-{2-[4-(4-trifluoromethyl-phenylamino)-7- (3-Trifluoromethyl-pyridin-2-yl)-quinazolin-2-yl]-ethyl}-piperidine-4-carboxylic acid amide; 1-{3-[4-(4-trifluoro Methyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-yl]-propyl}-piperidin-4-ol; 1-{3- [4-(4-Trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-yl]-propyl}-piperidine-3 -alcohol; 1-{4-[2-(2,6-dimethyl-morpholin-4-ylmethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[ 3,2-d]pyrimidin-4-ylamino]-phenyl}-ethanone (cis); 1-{4-[4-(4-trifluoromethyl-phenylamino)-7-(3- Trifluoromethyl-pyridin-2-yl)-quinazolin-2-yl]-piperidin-1-yl}-ethanone; 1-{4-[4-(4-trifluoromethyl-phenyl Amino)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-yl]-piperidin-1-yl}-propan-1-one; 1-{4-[7 -(3-Trifluoromethyl-pyridin-2-yl)-4-(6-trifluoromethyl-pyridin-3-ylamino)-quinazolin-2-ylmethyl]-piperazine-1- Base}-ethanone; 1-pyrrolidin-1-yl-3-[4-(4-trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)- Quinazolin-2-yl]-propan-1-one; 2-(1-{3-[4-(4-trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridine -2-yl)-quinazolin-2-yl]-propyl}-piperidin-4-yl)-ethanol; 2-{[4-(4-tert-butyl-phenylamino)-7-( 3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-ylmethyl]-propyl-amino}-ethanol; 2-{[4-(4-trifluoromethyl-phenylamino )-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-ylmethyl]-amino}-ethanol; 2-{1-[4-(4-trifluoromethyl -phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-ylmethyl]-piperidin-4-yl}-ethanol; 2-{1-[ 7-(3-trifluoromethyl-pyridin-2-yl)-4-(6-trifluoromethyl-pyridin-3-ylamino)-quinazolin-2-ylmethyl]-piperidine-4 -yl}-ethanol; 2-{4-[4-(4-trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-3-ylamino)-quinazoline-2 -ylmethyl]-piperazin-1-yl}-ethanol; 2-{4-[7-(3-trifluoromethyl-pyridin-2-yl)-4-(6-trifluoromethyl-pyridine -3-ylamino)-quinazolin-2-ylmethyl]-piperazin-1-yl}-ethanol; 2-methyl-2-{[4-(4-trifluoromethyl-phenylamino )-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-ylmethyl]-amino}-propan-1-ol; 4-(4-trifluoromethyl-benzene Amino)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline-2-carboxylic acid dimethylamide; 4-(4-trifluoromethyl-phenylamino)-7 -(3-Trifluoromethyl-pyridin-2-yl)-quinazoline-2-carboxylic acid methylamide; 4-(4-trifluoromethyl-phenylamino)-7-(3-trifluoro Methyl-pyridin-2-yl)-quinazoline-2-carboxylic acid (2-dimethylamino-ethyl)-amide; 4-(4-trifluoromethyl-phenylamino)-7-( 3-trifluoromethyl-pyridin-2-yl)-quinazoline-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide; 4-{2-[4-(4-tri Fluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-yl]-ethyl}-piperazine-1-carbaldehyde; N, N, N'-trimethyl-N'-[4-(4-trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-yl Methyl]-propane-1,3-diamine; and N-[4-(4-trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-quinone Azolin-2-ylmethyl]-methanesulfonamide. 61、一种下式化合物61. A compound of the following formula
Figure A038024520044C1
Figure A038024520044C1
 或其医药上可接受的盐，其中or a pharmaceutically acceptable salt thereof, wherein V、X、W、Y及Z各自分别为N或CR1，其条件是V及X中的至少一个为N；V, X, W, Y and Z are each independently N or CR 1 with the proviso that at least one of V and X is N; R1在各次出现时分别是选自氢、卤原子、羟基、氰基、氨基、C1-C8烷基、卤代C1-C8烷基、C1-C8烷氧基、卤代C1-C8烷氧基及一-(C1-C6烷基)氨基及二-(C1-C6烷基)氨基；R 1 is selected from hydrogen, halogen atom, hydroxyl, cyano, amino, C 1 -C 8 alkyl, halogenated C 1 -C 8 alkyl, C 1 -C 8 alkoxy, Halogenated C 1 -C 8 alkoxy and mono-(C 1 -C 6 alkyl)amino and di-(C 1 -C 6 alkyl)amino; Ar1及Ar2分别是选自苯基及5元至7元芳香族杂环，其各自为未经取代或被1至3个分别选自式LRa群组的取代基取代；Ar 1 and Ar 2 are respectively selected from phenyl and 5-7 membered aromatic heterocycles, each of which is unsubstituted or substituted by 1 to 3 substituents selected from the group of formula LRa ; L在各自出现时分别是选自键连接、-O-、-C(＝O)-、-OC(＝O)-、-C(＝O)O-、-O-C(＝O)O-、-S(O)m-、-NRx-、-C(＝O)NHRx-、-NHRxC(＝O)-、-NRxS(O)m-、S(O)mNRx-及-N[S(O)mRx]S(O)m-；其中m在各自出现时分别是选自0、1及2；以及Rx在各次出现时分别是选自氢及C1-C8烷基；L is selected from bond linkage, -O-, -C(=O)-, -OC(=O)-, -C(=O)O-, -OC(=O)O-, -OC(=O)O-, -S(O) m -, -NR x -, -C(=O)NHR x -, -NHR x C(=O)-, -NR x S(O) m -, S(O) m NR x - and -N[S(O) m R x ]S(O) m -; wherein m at each occurrence is selected from 0, 1 and 2; and R x at each occurrence is selected from hydrogen and C 1 -C 8 alkyl; Ra在各次出现时分别是选自：R a at each occurrence is selected from: (i)氢、卤原子、氰基及硝基；以及(i) hydrogen, halogen, cyano and nitro; and (ii)C1-C8烷基、C2-C8烯基、C2-C8炔基、C2-C8烷基醚、3元至10元杂环、一-及二-(C1-C8烷基)氨基及(3元至10元杂环)C1-C6烷基，(ii) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 2 -C 8 alkyl ether, 3- to 10-membered heterocycle, one- and two-( C 1 -C 8 alkyl) amino and (3-membered to 10-membered heterocycle) C 1 -C 6 alkyl, 其各自为未经取代或被1至9个分别选自Rb的取代基取代，R3是选自：Each of them is unsubstituted or substituted by 1 to 9 substituents respectively selected from R , R is selected from: (i)氢；(i) hydrogen; (ii)C1-C8烷基、C2-C8烯基、C2-C8炔基、C3-C8烷酮、C2-C8烷基醚、C6-C10芳基C0-C8烷基及5元至10元杂环C0-C8烷基，其各自任选地被1至9个分别选自Rb的取代基取代；以及(ii) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 alkanone, C 2 -C 8 alkyl ether, C 6 -C 10 aromatic group C 0 -C 8 alkyl and 5-membered to 10-membered heterocycle C 0 -C 8 alkyl, each of which is optionally substituted by 1 to 9 substituents respectively selected from R b ; and (iii)接合至R5或R6而形成一个4元至10元杂环基的基团，其为未经取代或被1至6个分别选自Rb的取代基取代；(iii) bonded to R 5 or R 6 to form a 4-membered to 10-membered heterocyclyl group, which is unsubstituted or substituted by 1 to 6 substituents selected from R respectively; R5及R6在各次出现时分别为：R 5 and R 6 are respectively: (i)各自分别选自：(i) each selected from: (a)氢或羟基；(a) hydrogen or hydroxyl; (b)C1-C8烷基，其为未经取代或被1至2个分别选自Rb的取代基取代；以及(b) C 1 -C 8 alkyl, which is unsubstituted or substituted by 1 to 2 substituents respectively selected from R b ; and (c)接合至R3而形成一个4元至10元杂环基团的基团，其为未经取代或被1至6个分别选自Rb的取代基取代；或(c) a group joined to R to form a 4- to 10-membered heterocyclic group, which is unsubstituted or substituted by 1 to 6 substituents independently selected from R ; or (ii)接合而形成一个3元至7元碳环或杂环，其为未经取代或被1至4个选自Rb的取代基取代；(ii) joined to form a 3-7 membered carbocyclic or heterocyclic ring, which is unsubstituted or substituted by 1 to 4 substituents selected from R b ; Rb在各次出现时分别是选自羟基、卤原子、氨基、氨基羰基、酰氨基、氰基、硝基、酮基、C1-C8烷基、C1-C8烷氧基、C1-C8烷硫基、C1-C8烷基醚、羟基C1-C8烷基、卤基C1-C8烷基、苯基、苯基(C1-C8烷基)、一-(C1-C6烷基)氨基及二-(C1-C6烷基)氨基、(SO2)C1-C8烷基、5元至7元杂环及(5元至7元杂环)(C1-C8烷基)；以及R b is selected from hydroxyl, halogen atom, amino, aminocarbonyl, amido, cyano, nitro, ketone, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 1 -C 8 alkyl ether, hydroxy C 1 -C 8 alkyl, halo C 1 -C 8 alkyl, phenyl, phenyl (C 1 -C 8 alkyl ), one-(C 1 -C 6 alkyl) amino and di-(C 1 -C 6 alkyl) amino, (SO 2 ) C 1 -C 8 alkyl, 5- to 7-membered heterocycle and (5 7-membered heterocycle) (C 1 -C 8 alkyl); and n为1、2或3。n is 1, 2 or 3. 62.如权利要求61所述的化合物或盐，其中V及X均为N。62. The compound or salt of claim 61, wherein V and X are both N. 63.如权利要求61所述的化合物或盐，其中W为N而Y与Z为CH。63. The compound or salt of claim 61, wherein W is N and Y and Z are CH. 64.如权利要求61所述的化合物或盐，其中Y为N以及W与Z为CH。64. The compound or salt of claim 61, wherein Y is N and W and Z are CH. 65.如权利要求61所述的化合物或盐，其中Z为N以及W与Y为CH。65. The compound or salt of claim 61, wherein Z is N and W and Y are CH. 66.如权利要求61所述的化合物或盐，其中W、Y及Z各自为CH。66. The compound or salt of claim 61, wherein W, Y and Z are each CH. 67.如权利要求61所述的化合物或盐，其中Ar1及Ar2分别是选自苯基及6元芳香族杂环，其各自被0、1或2个取代基取代。67. The compound or salt of claim 61, wherein Ar 1 and Ar 2 are respectively selected from phenyl and 6-membered aromatic heterocycles, each of which is substituted by 0, 1 or 2 substituents. 68.如权利要求67所述的化合物或盐，其中：68. The compound or salt of claim 67, wherein: (i)Ar1为苯基或吡啶基，其各自为未经取代或被1或2个选自卤原子、羟基、氰基、氨基、硝基、一-(C1-C6烷基)氨基及二-(C1-C6烷基)氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基及卤代C1-C6烷氧基的取代基取代；以及(i) Ar is phenyl or pyridyl, each of which is unsubstituted or replaced by 1 or 2 selected from halogen atoms, hydroxyl, cyano, amino, nitro, one-(C 1 -C 6 alkyl) Amino and di-(C 1 -C 6 alkyl) amino, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy and halogenated C 1 -C 6 alkane substituent substitution of oxy; and (ii)Ar2为苯基或吡啶基，其各自为未经取代或被1或2个分别选自卤原子、羟基、氰基、氨基、硝基、一-(C1-C6烷基)氨基及二-(C1-C6烷基)氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C2-C6烷基醚，C1-C6烷酰基、-(SO2)R2、-NRxS(O)m-及-N(S(Om)2的取代基取代；其中m为1或2，Rx为氢或C1-C6烷基以及R2为C1-C6烷基、卤代C1-C6烷基、氨基、一-或二-(C1-C6烷基)氨基或5元至10元N连接杂环基，各个R2任选地被Rb取代。(ii) Ar 2 is phenyl or pyridyl, each of which is unsubstituted or replaced by 1 or 2 selected from halogen atoms, hydroxyl, cyano, amino, nitro, one-(C 1 -C 6 alkyl ) amino and di-(C 1 -C 6 alkyl) amino, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 Substitution of alkoxy, C 2 -C 6 alkyl ether, C 1 -C 6 alkanoyl, -(SO 2 )R 2 , -NR x S(O) m - and -N(S(O m ) 2 where m is 1 or 2, R x is hydrogen or C 1 -C 6 alkyl and R 2 is C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, amino, mono- or di -(C 1 -C 6 alkyl)amino or 5- to 10-membered N-linked heterocyclyl, each R 2 is optionally substituted by R b . 69.如权利要求68所述的化合物或盐，其中：69. The compound or salt of claim 68, wherein: (i)Ar1为吡啶基，其为未经取代或被卤原子、C1-C4烷基或卤代C1-C4烷基取代；以及(i) Ar is pyridyl, which is unsubstituted or substituted by a halogen atom, C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl; and (ii)Ar2为苯基或吡啶基，未经取代或被C1-C4烷基、卤代C1-C4烷基、或-(SO2)R2-基团取代，其中R2为C1-C4烷基或卤代C1-C4烷基。(ii) Ar 2 is phenyl or pyridyl, unsubstituted or substituted by C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, or -(SO 2 )R 2 - group, wherein R 2 is C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl. 70.如权利要求69所述的化合物或盐，其中：70. The compound or salt of claim 69, wherein: (i)Ar1为吡啶-2-基、3-甲基-吡啶-2-基、3-三氟甲基-吡啶-2-基或3-卤-吡啶-2-基；以及(i) Ar is pyridin-2-yl, 3-methyl-pyridin-2-yl, 3-trifluoromethyl-pyridin-2-yl or 3-halo-pyridin-2-yl; and (ii)Ar2为苯基、2-吡啶基或3-吡啶基，其各自在4位置被三氟甲烷磺酰基、丙烷磺酰基、丙烷-2-磺酰基、叔丁基、三氟甲基或2，2，2-三氟-1-甲基-乙基取代。(ii) Ar 2 is phenyl, 2-pyridyl or 3-pyridyl, each of which is replaced at the 4 position by trifluoromethanesulfonyl, propanesulfonyl, propane-2-sulfonyl, tert-butyl, trifluoromethyl Or 2,2,2-trifluoro-1-methyl-ethyl substitution. 71.如权利要求61所述的化合物或盐，其中R3为：71. The compound or salt of claim 61, wherein R is: (i)氢；或(i) hydrogen; or (ii)C1-C8烷基、C2-C8烯基、苯基C0-C4烷基、5元至6元杂芳基C0-C4烷基、或4元至7元杂环烷基C0-C4烷基，其各自为未经取代或被1至4个分别选自羟基、卤原子、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基及卤代C1-C6烷氧基的取代基取代。(ii) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, phenyl C 0 -C 4 alkyl, 5-6 membered heteroaryl C 0 -C 4 alkyl, or 4-7 Membered heterocycloalkyl C 0 -C 4 alkyl, each of which is unsubstituted or replaced by 1 to 4 members selected from hydroxyl, halogen atom, amino, C 1 -C 6 alkyl, halogenated C 1 -C 6 Substituents of alkyl, C 1 -C 6 alkoxy and halogenated C 1 -C 6 alkoxy. 72.如权利要求71所述的化合物或盐，其中R3为：72. The compound or salt of claim 71, wherein R is: (i)氢；或(i) hydrogen; or (ii)C1-C6烷基或苄基，其各自为未经取代或被1至3个分别选自羟基、卤原子及C1-C4烷基的取代基取代。(ii) C 1 -C 6 alkyl or benzyl, each of which is unsubstituted or substituted with 1 to 3 substituents respectively selected from hydroxyl, halogen atom and C 1 -C 4 alkyl. 73.如权利要求61所述的化合物或盐，其中R5及R6各自分别是选自氢及C1-C6烷基。73. The compound or salt of claim 61, wherein R5 and R6 are each independently selected from hydrogen and C1 - C6 alkyl. 74.如权利要求73所述的化合物或盐，其中R5及R6各自为氢。74. The compound or salt of claim 73, wherein R and R are each hydrogen. 75.如权利要求61所述的化合物或盐，其中n为1。75. The compound or salt of claim 61, wherein n is 1. 76.如权利要求61所述的化合物或盐，其中：76. The compound or salt of claim 61, wherein: (i)V及X为N；(i) V and X are N; (ii)Ar1为吡啶基，其为未经取代或被卤原子、C1-C4烷基或卤代C1-C4烷基取代；(ii) Ar is pyridyl, which is unsubstituted or substituted by a halogen atom, C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl; (iii)Ar2为苯基或吡啶基，其为未经取代或被C1-C4烷基、卤代C1-C4烷基或式-(SO2)R2基团取代，其中R2为C1-C4烷基或卤代C1-C4烷基；(iii) Ar 2 is phenyl or pyridyl, which is unsubstituted or substituted by C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl or a group of formula -(SO 2 )R 2 , wherein R 2 is C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl; (iv)R3是选自(a)氢；以及(b)C1-C6烷基、C2-C6烯基及苯基C0-C4烷基，其各自被0、1或2个分别选自羟基、卤原子、C1-C4烷基及卤代C1-C4烷基的取代基取代；以及(iv) R 3 is selected from (a) hydrogen; and (b) C 1 -C 6 alkyl, C 2 -C 6 alkenyl and phenyl C 0 -C 4 alkyl, each of which is replaced by 0, 1 or Substituted by 2 substituents selected from hydroxyl, halogen atom, C 1 -C 4 alkyl and halogenated C 1 -C 4 alkyl; and (v)n为1。(v) n is 1. 77.如权利要求61所述的化合物或盐，其中该化合物是选自：77. The compound or salt of claim 61, wherein the compound is selected from: (1-甲烷磺酰基-2，3-二氢-1H-吲哚-5-基)-[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；(2，6-二甲基-吗啉-4-基)-(1-{4-[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基氨基]-苯基}-环丁基)-甲酮；(4-环己基-苯基)-[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-胺；(4-环戊基-苯基)-[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-胺；(4-环丙基-苯基)-[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；(4-乙基-苯基)-[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-胺；(4-异丙基-苯基)-[2-(2-甲氧基-乙基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；(4-异丙基-苯基)-[2-(四氢-吡喃-4-基氧基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；(4-异丙基-苯基)-[2-甲氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-胺；(4-异丙基-苯基)-[2-甲氧基甲基-7-(3-甲基-吡啶-2-基)-喹唑啉-4基]-胺；(4-异丙基-苯基)-[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-胺；(4-异丙基-苯基)-[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4基]-胺；(4-异丙基-苯基)-[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-胺；(4-异丙基-苯基)-[7-(3-甲基-吡啶-2-基)-2-四氢吡喃-4-基氧基甲基]-喹唑啉-4-基]-胺；(4-甲烷磺酰基-苯基)-[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4基]-胺；(4-甲烷磺酰基-苯基)-[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4基]-胺；(4-仲丁基-苯基)-[2-甲氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-胺；(4-仲丁基-苯基)-[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-胺；(4-仲丁基-苯基)-7-(3-甲基-吡啶-2-基)-2-(2-甲氧基-乙氧基甲基)-吡啶并[2，3-d]嘧啶-4-基]-胺；(4-仲丁基-苯基)-7-(3-甲基-吡啶-2-基)-2-甲氧基甲基-吡啶并[2，3-d]嘧啶-4-基]-胺；(4-叔丁基-苯基)-[2-(2-甲氧基-乙基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；(4-叔丁基-苯基)-[2-(3-二乙基氨基-1-甲基-丙氧基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；(4-叔丁基-苯基)-[2-(3-二乙基氨基-1-甲基-丙氧基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；(4-叔丁基-苯基)-[2-(3-二乙基氨基-丙氧基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；(4-叔丁基-苯基)-[2-(3-二甲基氨基-丙氧基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；(4-叔丁基-苯基)-[2-(3-吗啉-4-基-丙氧基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；(4-叔丁基-苯基)-[2-(4-二甲基氨基-丁氧基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；(4-叔丁基-苯基)-[2-(4-吗啉-4-基-丁氧基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；(4-叔丁基-苯基)-[2-异丁氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-胺；(4-叔丁基-苯基)-[2-异丁氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]-嘧啶-4-基]-胺；(4-叔丁基-苯基)-[2-甲氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-胺；(4-叔丁基-苯基)-[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-胺；(4-叔丁基-苯基)-[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；(4-叔丁基-苯基)-[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-胺；(4-叔丁基-苯基)-7-(3-氯-吡啶-2-基)-2-(2-甲氧基-乙氧基甲基)-吡啶并[2，3-d]嘧啶-4-基]-胺；(4-叔丁基-苯基)-7-(3-氯-吡啶-2-基)-2-乙氧基甲基-吡啶并[2，3-d]嘧啶-4-基]-胺；(4-叔丁基-苯基)-7-(3-氯-吡啶-2-基)-2-乙氧基甲基-喹唑啉-4-基]-胺；(4-叔丁基-苯基)-7-(3-氯-吡啶-2-基)-2-甲氧基甲基-吡啶并[2，3-d]嘧啶-4-基]-胺；(4-叔丁基-苯基)-7-(3-氯-吡啶-2-基)-2-甲氧基甲基-吡啶并[3，2-d]嘧啶-4-基]-胺；(4-叔丁基-苯基)-7-(3-氯-吡啶-2-基)-2-甲氧基甲基-喹唑啉-4-基]-胺；(6-叔丁基-吡啶-3-基)-[2-(2-甲氧基-乙基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；(6-叔丁基-吡啶-3-基)-[2-异丁氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-胺；(6-叔丁基-吡啶-3-基)-[2-异丁氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-胺；(6-叔丁基-吡啶-3-基)-[2-甲氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-胺；(6-叔丁基-吡啶-3-基)-[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；(6-叔丁基-吡啶-3-基)-[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-胺；(6-叔丁基-吡啶-3-基)-[7-(3-氯-吡啶-2-基)-2-乙氧基甲基-喹唑啉-4-基]-胺；(6-叔丁基-吡啶-3-基)-[7-(3-氯-吡啶-2-基)-2-异丁氧基甲基-吡啶并[2，3-d]嘧啶-4-基]-胺；(6-叔丁基-吡啶-3-基)-[7-(3-氯-吡啶-2-基)-2-甲氧基甲基-喹唑啉-4-基]-胺；(6-叔丁基-吡啶-3-基)-[7-(3-氯-吡啶-2-基)-2-甲氧基甲基-吡啶并[2，3-d]嘧啶-4-基]-胺；[2-(1-甲基-哌啶-4-基氧基甲基)-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(2-二乙基氨基-乙氧基甲基)-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(2-二甲基氨基-乙氧基甲基)-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(2-哌啶-1-基-乙氧基甲基)-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(3-苄氧基-丙基)-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(3-苄氧基-丙基)-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(3-苄氧基-丙基)-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-叔丁基-吡啶-3-基)-胺；[2-(3-二乙基氨基-丙氧基甲基)-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(3-二甲基氨基-2，2-二甲基-丙氧基甲基)-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(3-二甲基氨基-丙氧基甲基)-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-(吡啶-3-基甲氧基甲基)-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(吡啶-4-基甲氧基甲基)-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-(四氢-吡喃-4-基氧基甲基)-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基乙基-苯基)-胺；[2-(四氢-吡喃-4-基氧基甲基)-[7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-苄氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-[4-(2，2，2-三氟-1-甲基-乙基)-苯基]-胺；[2-苄氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-苄氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-苄氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(5-三氟甲基-吡啶-2-基)-胺；[2-苄氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲氧基-苯基)-胺；[2-苄氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲烷磺酰基-苯基)-胺；[2-苄氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-甲烷磺酰基-苯基)-胺；[2-苄氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-[4-(2-甲氧基-1，1-二甲基-乙基)-苯基]-胺；[2-苄氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-叔丁基-苯基)-胺；[2-苄氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(1-甲烷磺酰基-2，3-二氢-1H-吲哚-5-基)-胺；[2-环戊氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-[4-(吗啉-4-磺酰基)-苯基]-胺；[2-环丙基甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-[4-(吗啉-4-磺酰基)-苯基]-胺；[2-乙氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；[2-乙氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-异丙基-苯基)-胺；[2-乙氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲烷磺酰基-苯基)-胺；[2-乙氧基甲基-7-(3-甲基-吡啶-2-基)-喹唑啉-4-基]-(4-异丙基-苯基)-胺；[2-乙氧基甲基-7-(3-甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-乙氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；[2-乙氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-乙氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-乙氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-[4-(吗啉-4-磺酰基)-苯基]-胺；[2-乙氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-异丁氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-异丙基-苯基)-胺；[2-异丁氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；[2-异丁氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(3-甲基-4-三氟甲基-苯基)-胺；[2-异丁氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲氧基-苯基)-胺；[2-异丁氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-[4-(2-甲氧基-1，1-二甲基-乙基)-苯基]-胺；[2-异丁氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-甲烷磺酰基-苯基)-胺；[2-异丁氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-异丙基-苯基)-胺；[2-异丁氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；[2-异丁氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(3-甲基-三氟甲基-苯基)-胺；[2-异丁氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲烷磺酰基-苯基)-胺；[2-异丁氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲氧基-苯基)-胺；[2-异丁氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-甲烷磺酰基-苯基)-胺；[2-异丙氧基甲基-7-(3-甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-异丙氧基甲基-7-(3-甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-异丙氧基甲基-7-(3-甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-异丙氧基甲基-7-(3-甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-甲氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；[2-甲氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-甲氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲烷磺酰基-苯基)-胺；[2-甲氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲烷磺酰基-苯基)-胺；[2-甲氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲氧基-苯基)-胺；[2-甲氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(3-甲基-4-三氟甲基-苯基)-胺；[2-甲氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-[4-(2，2，2-三氟-1-甲基-乙基)-苯基]-胺；[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲烷磺酰基-苯基)-胺；[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-[4-(吗啉-4-磺酰基)-苯基]-胺；[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(3-甲基-4-三氟甲基-苯基)-胺；[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲氧基-苯基)-胺；[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-(4-吗啉-4-基-苯基)-胺；[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(4-三氟甲烷磺酰基-苯基)-胺；[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-(5-三氟甲基-吡啶-2-基)-胺；[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-[4-(吗啉-4-磺酰基)-苯基]-胺；[4-(2-二乙基氨基-1，1-二甲基-乙基)-苯基]-[2-甲氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基]-胺；[4-(2-甲氧基-1，1-二甲基-乙基)-苯基]-[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；[4-(2-甲氧基-1，1-二甲基-乙基)-苯基]-[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基]-胺；[4-(4-异丙基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基]-甲醇；[4-(4-叔丁基-苯基氨基)-7-(3-氟-吡啶-2-基)-喹唑啉-2-基]-甲醇；[4-(4-叔丁基-苯基氨基)-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-2-基]-甲醇；[4-(4-叔丁基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基]-甲醇；[4-(4-叔丁基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-2-基]-甲醇；[4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基]-甲醇；[4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-2-基]-甲醇；[4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-2-基]-甲醇；[4-(吗啉-4-磺酰基)-苯基]-[2-(四氢-吡喃-4-基氧基甲基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基]-胺；[4-(4-(哌啶-1-磺酰基)-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基]-甲醇；[4-(4-(哌啶-1-磺酰基)-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-2-基]-甲醇；[7-(3-氯-吡啶-2-基)-2-(2-甲氧基-乙氧基甲基)-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；[7-(3-氯-吡啶-2-基)-2-(2-甲氧基-乙氧基甲基)-吡啶并[2，3-d]嘧啶-4-基]-(4-异丙基-苯基)-胺；[7-(3-氯-吡啶-2-基)-2-(2-甲氧基-乙基)-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；[7-(3-氯-吡啶-2-基)-2-(四氢吡喃-4-基氧基甲基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[7-(3-氯-吡啶-2-基)-2-(四氢吡喃-4-基氧基甲基)-喹唑啉-4-基]-(4-异丙基-苯基)-胺；[7-(3-氯-吡啶-2-基)-2-乙氧基甲基-吡啶并[2，3-d]嘧啶-4-基]-(4-异丙基-苯基)-胺；[7-(3-氯-吡啶-2-基)-2-乙氧基甲基-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；[7-(3-氯-吡啶-2-基)-2-乙氧基甲基-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲烷磺酰基-苯基)-胺；[7-(3-氯-吡啶-2-基)-2-乙氧基甲基-吡啶并[2，3-d]嘧啶-4-基]-[4-(2，2，2-三氟-1-甲基-乙基)-苯基]-胺；[7-(3-氯-吡啶-2-基)-2-乙氧基甲基-吡啶并[2，3-d]嘧啶-4-基]-(4-环戊基-苯基)-胺；[7-(3-氯-吡啶-2-基)-2-乙氧基甲基-吡啶并[2，3-d]嘧啶-4-基]-(6-三氟甲基-吡啶-1-基)-胺；[7-(3-氯-吡啶-2-基)-2-乙氧基甲基-吡啶并[2，3-d]嘧啶-4-基]-(3-甲基-4-三氟甲基-苯基)-胺；[7-(3-氯-吡啶-2-基)-2-乙氧基甲基-喹唑啉-4-基]-(4-异丙基-苯基)-胺；[7-(3-氯-吡啶-2-基)-2-乙氧基甲基-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[7-(3-氯-吡啶-2-基)-2-异丁氧基甲基-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；[7-(3-氯-吡啶-2-基)-2-异丁氧基甲基-吡啶并[2，3-d]嘧啶-4-基]-(6-三氟甲基-吡啶-3-基)-胺；[7-(3-氯-吡啶-2-基)-2-异丁氧基甲基-吡啶并[2，3-d]嘧啶-4-基]-(3-甲基-4-三氟甲基-苯基)-胺；[7-(3-氯-吡啶-2-基)-2-异丁氧基甲基-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲氧基-苯基)-胺；[7-(3-氯-吡啶-2-基)-2-异丁氧基甲基-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲烷磺酰基-苯基)-胺；[7-(3-氯-吡啶-2-基)-2-异丁氧基甲基-吡啶并[2，3-d]嘧啶-4-基]-(4-甲烷磺酰基-苯基)-胺；[7-(3-氯-吡啶-2-基)-2-甲氧基甲基-吡啶并[2，3-d]嘧啶-4-基]-(4-异丙基-苯基)-胺；[7-(3-氯-吡啶-2-基)-2-甲氧基甲基-吡啶并[2，3-d]嘧啶-4-基]-[4-(2-甲氧基-1，1-二甲基-乙基)-苯基]-胺；[7-(3-氯-吡啶-2-基)-2-甲氧基甲基-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲氧基-苯基)-胺；[7-(3-氯-吡啶-2-基)-2-甲氧基甲基-吡啶并[2，3-d]嘧啶-4-基]-(3-甲基-4-三氟甲基-苯基)-胺；[7-(3-氯-吡啶-2-基)-2-甲氧基甲基-吡啶并[3，2-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；[7-(3-氯-吡啶-2-基)-2-甲氧基甲基-吡啶并[3，2-d]嘧啶-4-基]-(4-异丙基-苯基)-胺[7-(3-氯-吡啶-2-基)-2-甲氧基甲基-吡啶并[3，2-d]嘧啶-4-基]-[4-(吗啉-4-磺酰基)-苯基]-胺；[7-(3-氯-吡啶-2-基)-2-甲氧基甲基-喹唑啉-4-基]-(4-异丙基-苯基)-胺；[7-(3-氯-吡啶-2-基)-2-甲氧基甲基-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[7-(3-氯-吡啶-2-基)-4-(4-异丙基-苯基氨基)-喹唑啉-2-基]-甲醇；[7-(3-氯-吡啶-2-基)-4-(4-三氟甲基-苯基氨基)-吡啶并[3，2-d]嘧啶-2-基]-甲醇；[7-(3-甲基-吡啶-2-基)-2-(四氢呋喃-3-基)-吡啶并[2，3-d]嘧啶-4-基]-(4-三氟甲基-苯基)-胺；[7-(3-甲基-吡啶-2-基)-2-(四氢吡喃-4-基氧基甲基)-喹唑啉-4-基]-(4-三氟甲基-苯基)-胺；[7-(3-甲基-吡啶-2-基)-4-(4-三氟甲基-苯基氨基)-吡啶并[2，3-d]嘧啶-2-基]-甲醇；[7-(3-三氟甲基-吡啶-2-基)-4-(6-三氟甲基-吡啶-3-基氨基)-喹唑啉-2-基]-甲醇；1-{4-[2-异丁氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基氨基]-苯基}-环丁烷甲腈；1-{4-[2-甲氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基氨基]-苯基}-环丁烷甲腈；1-{4-[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基氨基]-苯基}-乙酮；1-{4-[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基氨基]-苯基}-丁-1-酮；1-{4-[7-(3-氯-吡啶-2-基)-2-乙氧基甲基-吡啶并[2，3-d]嘧啶-4-基氨基]-苯基}-环丁烷甲腈；1-二甲基氨基-3-[4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基甲氧基]-丙-2-醇；2-[4-(4-叔丁基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基]-2-甲基-丙-1-醇；1-{4-[2-苄氧甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基氨基]-苯基}-2-甲基-丙腈；2-{4-[2-乙氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基氨基]-苯基}-2-甲基-丙腈；2-{4-[2-丁氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基氨基]-苯基}-2-甲基-丙腈；2-{4-[2-丁氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基氨基]-苯基}-2-甲基-丙腈；2-{4-[2-甲氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基氨基]-苯基}-2-甲基-丙腈；2-{4-[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基氨基]-苯基}-2-甲基-丙腈；2-{4-[7-(3-氯-吡啶-2-基)-2-(2-甲氧基-乙氧基甲基)-吡啶并[2，3-d]嘧啶-4-基氨基]-苯基}-2-甲基-丙腈；2-{4-[7-(3-氯-吡啶-2-基)-2-异丁氧基甲基-吡啶并[2，3-d]嘧啶-4-基氨基]-苯基}-2-甲基-丙腈；2-{4-[7-(3-氯-吡啶-2-基)-2-甲氧基甲基-吡啶并[2，3-d]嘧啶-4-基氨基]-苯基}-2-甲基-丙腈；2-甲基-2-[4-(4-三氟甲基-苯基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基]-丙-1-醇；2-甲基-2-{4-[7-(3-甲基-吡啶-2-基)-2-(四氢呋喃-3-基)-吡啶并[2，3-d]嘧啶-4-基氨基]-苯基}-丙腈；3-[4-(6-叔丁基-吡啶-3-基氨基)-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-2-基]-丙-1-醇；3-[7-(3-三氟甲基-吡啶-2-基)-4-(6-三氟甲基-吡啶-3-基氨基)-喹唑啉-2-基]-丙-1-醇；3-{4-[2-异丁氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基氨基]-苯基}-3-甲基-丁-2-酮；3-{4-[2-异丁氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基氨基]-苯基}-3-甲基-丁-2-酮；3-{4-[2-甲氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基氨基]-苯基}-3-甲基-丁-2-酮；3-{4-[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基氨基]-苯基}-3-甲基-丁-2-酮；3-{4-[7-(3-氯-吡啶-2-基)-2-异丁氧基甲基-吡啶并[2，3-d]嘧啶-4-基氨基]-苯基}-3-甲基-丁-2-酮；3-{4-[7-(3-氯-吡啶-2-基)-2-甲氧基甲基-吡啶并[2，3-d]嘧啶-4-基氨基]-苯基}-3-甲基-丁-2-酮；4-[2-苄氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基氨基]-N-叔丁基苯磺酰胺；4-[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基氨基]-苄腈；N，N-二乙基-2-{4-[2-异丁氧基甲基-7-(3-甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基氨基]-苯基}-异丁酰胺；N，N-二乙基-2-{4-[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[2，3-d]嘧啶-4-基氨基]-苯基}-异丁酰胺；N-叔丁基-4-[2-羟基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基氨基]-N-甲基-苯磺酰胺；N-叔丁基-4-[2-羟基甲基-7-(3-三氟甲基-吡啶-2-基)-吡啶并[3，2-d]嘧啶-4-基氨基]-N-甲基-苯磺酰胺；以及N-叔丁基-4-[2-甲氧基甲基-7-(3-三氟甲基-吡啶-2-基)-喹唑啉-4-基氨基]-苯磺酰胺。(1-Methanesulfonyl-2,3-dihydro-1H-indol-5-yl)-[2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)- Quinazolin-4-yl]-amine; (2,6-Dimethyl-morpholin-4-yl)-(1-{4-[2-methoxymethyl-7-(3-trifluoro Methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-ylamino]-phenyl}-cyclobutyl)-methanone; (4-cyclohexyl-phenyl)-[ 2-Methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-yl]-amine; (4-cyclopentyl- Phenyl)-[2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-amine; (4 -cyclopropyl-phenyl)-[2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine; (4-ethyl Base-phenyl)-[2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-yl]-amine; (4-isopropyl-phenyl)-[2-(2-methoxy-ethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl] -amine; (4-isopropyl-phenyl)-[2-(tetrahydro-pyran-4-yloxymethyl)-7-(3-trifluoromethyl-pyridin-2-yl)- Quinazolin-4-yl]-amine; (4-isopropyl-phenyl)-[2-methoxymethyl-7-(3-methyl-pyridin-2-yl)-pyrido[2 , 3-d]pyrimidin-4-yl]-amine; (4-isopropyl-phenyl)-[2-methoxymethyl-7-(3-methyl-pyridin-2-yl)-quinone Azolin-4-yl]-amine; (4-isopropyl-phenyl)-[2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3 ,2-d]pyrimidin-4-yl]-amine; (4-isopropyl-phenyl)-[2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl) -quinazolin-4-yl]-amine; (4-isopropyl-phenyl)-[2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido [2,3-d]pyrimidin-4-yl]-amine; (4-isopropyl-phenyl)-[7-(3-methyl-pyridin-2-yl)-2-tetrahydropyran- 4-yloxymethyl]-quinazolin-4-yl]-amine; (4-methanesulfonyl-phenyl)-[2-methoxymethyl-7-(3-trifluoromethyl- Pyridin-2-yl)-quinazolin-4-yl]-amine; (4-methanesulfonyl-phenyl)-[2-methoxymethyl-7-(3-trifluoromethyl-pyridine-2 -yl)-pyrido[2,3-d]pyrimidin-4-yl]-amine; (4-sec-butyl-phenyl)-[2-methoxymethyl-7-(3-methyl-pyridine -2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-amine; (4-sec-butyl-phenyl)-[2-methoxymethyl-7-(3-tri Fluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-amine; (4-sec-butyl-phenyl)-7-(3-methyl-pyridine- 2-yl)-2-(2-methoxy-ethoxymethyl)-pyrido[2,3-d]pyrimidin-4-yl]-amine; (4-sec-butyl-phenyl)- 7-(3-Methyl-pyridin-2-yl)-2-methoxymethyl-pyrido[2,3-d]pyrimidin-4-yl]-amine; (4-tert-butyl-phenyl )-[2-(2-Methoxy-ethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine; (4-tert-butyl -Phenyl)-[2-(3-Diethylamino-1-methyl-propoxymethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline-4 -yl]-amine; (4-tert-butyl-phenyl)-[2-(3-diethylamino-1-methyl-propoxymethyl)-7-(3-trifluoromethyl- Pyridin-2-yl)-quinazolin-4-yl]-amine; (4-tert-butyl-phenyl)-[2-(3-diethylamino-propoxymethyl)-7-( 3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine; (4-tert-butyl-phenyl)-[2-(3-dimethylamino-propoxy Methyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine; (4-tert-butyl-phenyl)-[2-(3-mol Lin-4-yl-propoxymethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine; (4-t-butyl-phenyl )-[2-(4-Dimethylamino-butoxymethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine; (4 -tert-butyl-phenyl)-[2-(4-morpholin-4-yl-butoxymethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline- 4-yl]-amine; (4-tert-butyl-phenyl)-[2-isobutoxymethyl-7-(3-methyl-pyridin-2-yl)-pyrido[2,3- d] pyrimidin-4-yl]-amine; (4-tert-butyl-phenyl)-[2-isobutoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyridine And[2,3-d]-pyrimidin-4-yl]-amine; (4-tert-butyl-phenyl)-[2-methoxymethyl-7-(3-methyl-pyridine-2- base)-pyrido[2,3-d]pyrimidin-4-yl]-amine; (4-tert-butyl-phenyl)-[2-methoxymethyl-7-(3-trifluoromethyl -pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-yl]-amine; (4-tert-butyl-phenyl)-[2-methoxymethyl-7-(3 -trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine; (4-tert-butyl-phenyl)-[2-methoxymethyl-7-(3-tri Fluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-amine; (4-tert-butyl-phenyl)-7-(3-chloro-pyridine-2 -yl)-2-(2-methoxy-ethoxymethyl)-pyrido[2,3-d]pyrimidin-4-yl]-amine; (4-tert-butyl-phenyl)-7 -(3-Chloro-pyridin-2-yl)-2-ethoxymethyl-pyrido[2,3-d]pyrimidin-4-yl]-amine; (4-tert-butyl-phenyl)- 7-(3-Chloro-pyridin-2-yl)-2-ethoxymethyl-quinazolin-4-yl]-amine; (4-tert-butyl-phenyl)-7-(3-chloro -pyridin-2-yl)-2-methoxymethyl-pyrido[2,3-d]pyrimidin-4-yl]-amine; (4-tert-butyl-phenyl)-7-(3- Chloro-pyridin-2-yl)-2-methoxymethyl-pyrido[3,2-d]pyrimidin-4-yl]-amine; (4-tert-butyl-phenyl)-7-(3 -Chloro-pyridin-2-yl)-2-methoxymethyl-quinazolin-4-yl]-amine; (6-tert-butyl-pyridin-3-yl)-[2-(2-methyl Oxygen-ethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine; (6-tert-butyl-pyridin-3-yl)-[ 2-isobutoxymethyl-7-(3-methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-amine; (6-tert-butyl-pyridine -3-yl)-[2-isobutoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-amine ; (6-tert-butyl-pyridin-3-yl)-[2-methoxymethyl-7-(3-methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidine- 4-yl]-amine; (6-tert-butyl-pyridin-3-yl)-[2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline -4-yl]-amine; (6-tert-butyl-pyridin-3-yl)-[2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido [2,3-d]pyrimidin-4-yl]-amine; (6-tert-butyl-pyridin-3-yl)-[7-(3-chloro-pyridin-2-yl)-2-ethoxy Methyl-quinazolin-4-yl]-amine; (6-tert-butyl-pyridin-3-yl)-[7-(3-chloro-pyridin-2-yl)-2-isobutoxymethyl Base-pyrido[2,3-d]pyrimidin-4-yl]-amine; (6-tert-butyl-pyridin-3-yl)-[7-(3-chloro-pyridin-2-yl)-2 -Methoxymethyl-quinazolin-4-yl]-amine; (6-tert-butyl-pyridin-3-yl)-[7-(3-chloro-pyridin-2-yl)-2-methan Oxymethyl-pyrido[2,3-d]pyrimidin-4-yl]-amine; [2-(1-methyl-piperidin-4-yloxymethyl)-[7-(3- Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-(2-diethylamino-ethyl Oxymethyl)-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-(2-Dimethylamino-ethoxymethyl)-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoro Methyl-phenyl)-amine; [2-(2-piperidin-1-yl-ethoxymethyl)-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline -4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-(3-benzyloxy-propyl)-[7-(3-trifluoromethyl-pyridine- 2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(3-benzyloxy-propyl)-[7-(3-trifluoro Methyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-(3-benzyloxy-propyl)- [7-(3-Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-tert-butyl-pyridin-3-yl)-amine; [2-(3-Di Ethylamino-propoxymethyl)-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)- Amine; [2-(3-Dimethylamino-2,2-dimethyl-propoxymethyl)-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline- 4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(3-dimethylamino-propoxymethyl)-[7-(3-trifluoromethyl-pyridine- 2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-(pyridin-3-ylmethoxymethyl)-[7-(3- Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-(pyridin-4-ylmethoxy Methyl)-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2 -(tetrahydro-pyran-4-yloxymethyl)-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl [2-(tetrahydro-pyran-4-yloxymethyl)-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline -4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-benzyloxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinone Azolin-4-yl]-[4-(2,2,2-trifluoro-1-methyl-ethyl)-phenyl]-amine; [2-benzyloxymethyl-7-(3- Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-benzyloxymethyl-7-(3-tri Fluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-benzyloxymethyl-7-(3 -trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine; [2-benzyloxymethyl-7- (3-Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethoxy-phenyl)-amine; [2-benzyloxymethyl-7- (3-Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine; [2-benzyloxymethyl-7- (3-Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-methanesulfonyl-phenyl)-amine; [2-benzyloxymethyl-7-(3 -trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-[4-(2-methoxy-1,1-dimethyl-ethyl)-phenyl]-amine; [2-Benzyloxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-tert-butyl-phenyl)-amine; [2 -Benzyloxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(1-methanesulfonyl-2,3-dihydro-1H-ind Indol-5-yl)-amine; [2-cyclopentyloxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-[4-( Line-4-sulfonyl)-phenyl]-amine; [2-cyclopropylmethoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl ]-[4-(morpholine-4-sulfonyl)-phenyl]-amine; [2-ethoxymethyl-7-(3-methyl-pyridin-2-yl)-pyrido[2, 3-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-ethoxymethyl-7-(3-methyl-pyridin-2-yl)-pyridine [2,3-d]pyrimidin-4-yl]-(4-isopropyl-phenyl)-amine; [2-ethoxymethyl-7-(3-methyl-pyridin-2-yl )-pyrido[2,3-d]pyrimidin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine; [2-ethoxymethyl-7-(3-methyl- Pyridin-2-yl)-quinazolin-4-yl]-(4-isopropyl-phenyl)-amine; [2-ethoxymethyl-7-(3-methyl-pyridine-2- Base)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-ethoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl )-pyrido[2,3-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-ethoxymethyl-7-(3-trifluoromethyl -pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-ethoxymethyl- 7-(3-Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-Ethoxymethyl-7 -(3-Trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-[4-(morpholine-4-sulfonyl)-phenyl]-amine; [2-ethoxy Methyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-iso Butoxymethyl-7-(3-methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-(4-isopropyl-phenyl)-amine; [2-Isobutoxymethyl-7-(3-methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-(4-trifluoromethyl-benzene base)-amine; [2-isobutoxymethyl-7-(3-methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-(3-methyl [2-isobutoxymethyl-7-(3-methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidine -4-yl]-(4-trifluoromethoxy-phenyl)-amine; [2-isobutoxymethyl-7-(3-methyl-pyridin-2-yl)-pyrido[2 , 3-d] pyrimidin-4-yl]-[4-(2-methoxy-1,1-dimethyl-ethyl)-phenyl]-amine; [2-isobutoxymethyl- 7-(3-Methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amine; [2-isobutoxy Cylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-(4-isopropyl-phenyl)-amine; [2-Isobutoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-(4-trifluoromethyl -phenyl)-amine; [2-isobutoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]- (3-Methyl-trifluoromethyl-phenyl)-amine; [2-isobutoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3 -d]pyrimidin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine; [2-isobutoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl )-pyrido[2,3-d]pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine; [2-isobutoxymethyl-7-(3-trifluoro Methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amine; [2-isopropoxymethyl-7 -(3-Methyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-isopropoxymethyl-7-( 3-Methyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-isopropoxymethyl-7-(3- Methyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-isopropoxymethyl-7-(3-methyl -pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-methoxymethyl-7-(3-methyl -pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-methoxymethyl-7-( 3-Methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-methoxy Methyl-7-(3-methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine; [2-Methoxymethyl-7-(3-methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-(4-trifluoromethanesulfonyl-benzene base)-amine; [2-methoxymethyl-7-(3-methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-(4-trifluoro Methoxy-phenyl)-amine; [2-methoxymethyl-7-(3-methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]- (3-methyl-4-trifluoromethyl-phenyl)-amine; [2-methoxymethyl-7-(3-methyl-pyridin-2-yl)-pyrido[2,3- d] pyrimidin-4-yl]-[4-(2,2,2-trifluoro-1-methyl-ethyl)-phenyl]-amine; [2-methoxymethyl-7-(3 -trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [2-methoxymethyl Base-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine; [2-Methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-[4-(morpholine-4 -sulfonyl)-phenyl]-amine; [2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidine-4- base]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2 ,3-d]pyrimidin-4-yl]-(3-methyl-4-trifluoromethyl-phenyl)-amine; [2-methoxymethyl-7-(3-trifluoromethyl- Pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine; [2-methoxymethyl-7-( 3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [2- Methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-yl]-(4-morpholin-4-yl-benzene base)-amine; [2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl )-amine; [2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(6-trifluoromethyl-pyridine-3 -yl)-amine; [2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethanesulfonyl- phenyl)-amine; [2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(5-trifluoromethyl-pyridine -2-yl)-amine; [2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-[4-(morpholine- 4-sulfonyl)-phenyl]-amine; [4-(2-diethylamino-1,1-dimethyl-ethyl)-phenyl]-[2-methoxymethyl-7- (3-Methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-yl]-amine; [4-(2-methoxy-1,1-dimethyl-ethyl Base)-phenyl]-[2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine; [4-(2- Methoxy-1,1-dimethyl-ethyl)-phenyl]-[2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3 , 2-d] pyrimidin-4-yl]-amine; [4-(4-isopropyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline- 2-yl]-methanol; [4-(4-tert-butyl-phenylamino)-7-(3-fluoro-pyridin-2-yl)-quinazolin-2-yl]-methanol; [4- (4-tert-butyl-phenylamino)-7-(3-methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-2-yl]-methanol; [4-(4 -tert-butyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-yl]-methanol; [4-(4-tert-butyl-phenyl Amino)-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-2-yl]-methanol; [4-(4-trifluoromethyl-benzene [4-(4-trifluoromethyl-phenylamino)-7- (3-Trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-2-yl]-methanol; [4-(4-trifluoromethyl-phenylamino)-7 -(3-Trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-2-yl]-methanol; [4-(morpholine-4-sulfonyl)-phenyl] -[2-(tetrahydro-pyran-4-yloxymethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine; [4 -(4-(piperidine-1-sulfonyl)-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-yl]-methanol; [4- (4-(piperidine-1-sulfonyl)-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-2-yl] -methanol; [7-(3-chloro-pyridin-2-yl)-2-(2-methoxy-ethoxymethyl)-pyrido[2,3-d]pyrimidin-4-yl]- (4-trifluoromethyl-phenyl)-amine; [7-(3-chloro-pyridin-2-yl)-2-(2-methoxy-ethoxymethyl)-pyrido[2, 3-d]pyrimidin-4-yl]-(4-isopropyl-phenyl)-amine; [7-(3-chloro-pyridin-2-yl)-2-(2-methoxy-ethyl )-pyrido[2,3-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [7-(3-chloro-pyridin-2-yl)-2-( Tetrahydropyran-4-yloxymethyl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [7-(3-chloro-pyridin-2-yl )-2-(tetrahydropyran-4-yloxymethyl)-quinazolin-4-yl]-(4-isopropyl-phenyl)-amine; [7-(3-chloro-pyridine -2-yl)-2-ethoxymethyl-pyrido[2,3-d]pyrimidin-4-yl]-(4-isopropyl-phenyl)-amine; [7-(3-chloro -pyridin-2-yl)-2-ethoxymethyl-pyrido[2,3-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [7-( 3-Chloro-pyridin-2-yl)-2-ethoxymethyl-pyrido[2,3-d]pyrimidin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine; [7-(3-Chloro-pyridin-2-yl)-2-ethoxymethyl-pyrido[2,3-d]pyrimidin-4-yl]-[4-(2,2,2-tri Fluoro-1-methyl-ethyl)-phenyl]-amine; [7-(3-chloro-pyridin-2-yl)-2-ethoxymethyl-pyrido[2,3-d]pyrimidine -4-yl]-(4-cyclopentyl-phenyl)-amine; [7-(3-chloro-pyridin-2-yl)-2-ethoxymethyl-pyrido[2,3-d ]pyrimidin-4-yl]-(6-trifluoromethyl-pyridin-1-yl)-amine; [7-(3-chloro-pyridin-2-yl)-2-ethoxymethyl-pyrido [2,3-d]pyrimidin-4-yl]-(3-methyl-4-trifluoromethyl-phenyl)-amine; [7-(3-chloro-pyridin-2-yl)-2- Ethoxymethyl-quinazolin-4-yl]-(4-isopropyl-phenyl)-amine; [7-(3-chloro-pyridin-2-yl)-2-ethoxymethyl -quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [7-(3-chloro-pyridin-2-yl)-2-isobutoxymethyl-pyrido [2,3-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [7-(3-chloro-pyridin-2-yl)-2-isobutoxymethyl Base-pyrido[2,3-d]pyrimidin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine; [7-(3-chloro-pyridin-2-yl)- 2-isobutoxymethyl-pyrido[2,3-d]pyrimidin-4-yl]-(3-methyl-4-trifluoromethyl-phenyl)-amine; [7-(3- Chloro-pyridin-2-yl)-2-isobutoxymethyl-pyrido[2,3-d]pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine; [ 7-(3-Chloro-pyridin-2-yl)-2-isobutoxymethyl-pyrido[2,3-d]pyrimidin-4-yl]-(4-trifluoromethanesulfonyl-phenyl )-amine; [7-(3-chloro-pyridin-2-yl)-2-isobutoxymethyl-pyrido[2,3-d]pyrimidin-4-yl]-(4-methanesulfonyl -phenyl)-amine; [7-(3-chloro-pyridin-2-yl)-2-methoxymethyl-pyrido[2,3-d]pyrimidin-4-yl]-(4-iso Propyl-phenyl)-amine; [7-(3-Chloro-pyridin-2-yl)-2-methoxymethyl-pyrido[2,3-d]pyrimidin-4-yl]-[4 -(2-methoxy-1,1-dimethyl-ethyl)-phenyl]-amine; [7-(3-chloro-pyridin-2-yl)-2-methoxymethyl-pyridine [2,3-d]pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine; [7-(3-chloro-pyridin-2-yl)-2-methoxy Methyl-pyrido[2,3-d]pyrimidin-4-yl]-(3-methyl-4-trifluoromethyl-phenyl)-amine; [7-(3-chloro-pyridine-2- base)-2-methoxymethyl-pyrido[3,2-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [7-(3-chloro-pyridine -2-yl)-2-methoxymethyl-pyrido[3,2-d]pyrimidin-4-yl]-(4-isopropyl-phenyl)-amine[7-(3-chloro- Pyridin-2-yl)-2-methoxymethyl-pyrido[3,2-d]pyrimidin-4-yl]-[4-(morpholine-4-sulfonyl)-phenyl]-amine; [7-(3-Chloro-pyridin-2-yl)-2-methoxymethyl-quinazolin-4-yl]-(4-isopropyl-phenyl)-amine; [7-(3 -Chloro-pyridin-2-yl)-2-methoxymethyl-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [7-(3-chloro-pyridine -2-yl)-4-(4-isopropyl-phenylamino)-quinazolin-2-yl]-methanol; [7-(3-chloro-pyridin-2-yl)-4-(4 -trifluoromethyl-phenylamino)-pyrido[3,2-d]pyrimidin-2-yl]-methanol; [7-(3-methyl-pyridin-2-yl)-2-(tetrahydrofuran- 3-yl)-pyrido[2,3-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [7-(3-methyl-pyridin-2-yl) -2-(tetrahydropyran-4-yloxymethyl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine; [7-(3-methyl- Pyridin-2-yl)-4-(4-trifluoromethyl-phenylamino)-pyrido[2,3-d]pyrimidin-2-yl]-methanol; [7-(3-trifluoromethyl -pyridin-2-yl)-4-(6-trifluoromethyl-pyridin-3-ylamino)-quinazolin-2-yl]-methanol; 1-{4-[2-isobutoxymethyl Base-7-(3-methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-ylamino]-phenyl}-cyclobutanecarbonitrile; 1-{4-[ 2-Methoxymethyl-7-(3-methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-ylamino]-phenyl}-cyclobutanecarbonitrile; 1-{4-[2-Methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-ylamino]-phenyl }-ethanone; 1-{4-[2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-yl Amino]-phenyl}-butan-1-one; 1-{4-[7-(3-chloro-pyridin-2-yl)-2-ethoxymethyl-pyrido[2,3-d] Pyrimidin-4-ylamino]-phenyl}-cyclobutanecarbonitrile; 1-dimethylamino-3-[4-(4-trifluoromethyl-phenylamino)-7-(3-trifluoro Methyl-pyridin-2-yl)-quinazolin-2-ylmethoxy]-propan-2-ol; 2-[4-(4-tert-butyl-phenylamino)-7-(3- Trifluoromethyl-pyridin-2-yl)-quinazolin-2-yl]-2-methyl-propan-1-ol; 1-{4-[2-benzyloxymethyl-7-(3- Trifluoromethyl-pyridin-2-yl)-quinazolin-4-ylamino]-phenyl}-2-methyl-propionitrile; 2-{4-[2-ethoxymethyl-7- (3-Trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-ylamino]-phenyl}-2-methyl-propionitrile; 2-{4-[ 2-Butoxymethyl-7-(3-methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-ylamino]-phenyl}-2-methyl-propane Nitrile; 2-{4-[2-Butoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-ylamino]- Phenyl}-2-methyl-propionitrile; 2-{4-[2-methoxymethyl-7-(3-methyl-pyridin-2-yl)-pyrido[2,3-d] Pyrimidin-4-ylamino]-phenyl}-2-methyl-propionitrile; 2-{4-[2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl) -quinazolin-4-ylamino]-phenyl}-2-methyl-propionitrile; 2-{4-[7-(3-chloro-pyridin-2-yl)-2-(2-methoxy yl-ethoxymethyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-phenyl}-2-methyl-propionitrile; 2-{4-[7-(3-chloro -pyridin-2-yl)-2-isobutoxymethyl-pyrido[2,3-d]pyrimidin-4-ylamino]-phenyl}-2-methyl-propionitrile; 2-{4 -[7-(3-Chloro-pyridin-2-yl)-2-methoxymethyl-pyrido[2,3-d]pyrimidin-4-ylamino]-phenyl}-2-methyl- Propionitrile; 2-Methyl-2-[4-(4-trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-yl ]-propan-1-ol; 2-methyl-2-{4-[7-(3-methyl-pyridin-2-yl)-2-(tetrahydrofuran-3-yl)-pyrido[2,3 -d]pyrimidin-4-ylamino]-phenyl}-propionitrile; 3-[4-(6-tert-butyl-pyridin-3-ylamino)-7-(3-trifluoromethyl-pyridine- 2-yl)-quinazolin-2-yl]-propan-1-ol; 3-[7-(3-trifluoromethyl-pyridin-2-yl)-4-(6-trifluoromethyl- Pyridin-3-ylamino)-quinazolin-2-yl]-propan-1-ol; 3-{4-[2-isobutoxymethyl-7-(3-methyl-pyridine-2- Base)-pyrido[2,3-d]pyrimidin-4-ylamino]-phenyl}-3-methyl-butan-2-one; 3-{4-[2-isobutoxymethyl- 7-(3-Trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-ylamino]-phenyl}-3-methyl-butan-2-one; 3 -{4-[2-Methoxymethyl-7-(3-methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-ylamino]-phenyl}-3 -Methyl-butan-2-one; 3-{4-[2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d] Pyrimidin-4-ylamino]-phenyl}-3-methyl-butan-2-one; 3-{4-[7-(3-chloro-pyridin-2-yl)-2-isobutoxymethyl Base-pyrido[2,3-d]pyrimidin-4-ylamino]-phenyl}-3-methyl-butan-2-one; 3-{4-[7-(3-chloro-pyridine-2 -yl)-2-methoxymethyl-pyrido[2,3-d]pyrimidin-4-ylamino]-phenyl}-3-methyl-butan-2-one; 4-[2-benzyl Oxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-ylamino]-N-tert-butylbenzenesulfonamide; 4-[2-methoxymethyl Base-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[3,2-d]pyrimidin-4-ylamino]-benzonitrile; N,N-diethyl-2-{ 4-[2-Isobutoxymethyl-7-(3-methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidin-4-ylamino]-phenyl}-isobutyl Amide; N,N-Diethyl-2-{4-[2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d] Pyrimidin-4-ylamino]-phenyl}-isobutyramide; N-tert-butyl-4-[2-hydroxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazole Lin-4-ylamino]-N-methyl-benzenesulfonamide; N-tert-butyl-4-[2-hydroxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyridine and [3,2-d]pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide; and N-tert-butyl-4-[2-methoxymethyl-7-(3-trifluoro Methyl-pyridin-2-yl)-quinazolin-4-ylamino]-benzenesulfonamide. 78.如权利要求1、16、34或61中任一所述的化合物或盐，其中该化合物在辣椒辣素受体钙移动性检定分析中具有IC50值为100nM或以下。78. The compound or salt of any one of claims 1, 16, 34 or 61, wherein the compound has an IC50 value of 100 nM or less in a capsaicin receptor calcium mobility assay. 79.如权利要求1、16、34或61中任一所述的化合物或盐，其中该化合物在辣椒辣素受体钙移动性检定分析中具有IC50值为10nM或以下。79. The compound or salt of any one of claims 1, 16, 34 or 61, wherein the compound has an IC50 value of 10 nM or less in a capsaicin receptor calcium mobility assay. 80.如权利要求1、16、34或61中任一所述的化合物或盐，其中该化合物在辣椒辣素受体钙移动性检定分析中具有IC50值为1nM或以下。80. The compound or salt of any one of claims 1, 16, 34 or 61, wherein the compound has an IC50 value of 1 nM or less in a capsaicin receptor calcium mobility assay. 81、一种医药组合物，包含至少一种如权利要求1、16、34或61中任一所述的化合物或盐并结合一种生理上可接受的载剂或赋形剂。81. A pharmaceutical composition comprising at least one compound or salt according to any one of claims 1, 16, 34 or 61 in combination with a physiologically acceptable carrier or excipient. 82.如权利要求81所述的医药组合物，其中该组合物是调配成注射用流体、喷雾剂、乳膏剂、凝胶剂、丸粒剂、胶囊剂、糖浆剂或经皮贴片。82. The pharmaceutical composition of claim 81, wherein the composition is formulated as an injectable fluid, spray, cream, gel, pellet, capsule, syrup or transdermal patch. 83、一种降低细胞辣椒辣素受体的钙传导的方法，包含一种表达辣椒辣素受体的细胞与至少一种下式化合物或盐接触：83. A method of reducing calcium conductance of a capsaicin receptor in a cell comprising contacting a cell expressing a capsaicin receptor with at least one compound or salt of the formula:
Figure A038024520057C1
Figure A038024520057C1
 其中：in: V、X、W、Y及Z各自分别为N或CR1，其条件是V及X中的至少Each of V, X, W, Y, and Z is N or CR 1 , with the proviso that at least one of V and X 一个为N；U为N或CR2，但若V及X为N，则U为CR2；One is N; U is N or CR 2 , but if V and X are N, then U is CR 2 ; R1在各次出现时分别是选自氢、卤原子、羟基、氰基、氨基、C1-C8烷基、卤代C1-C8烷基、C1-C8烷氧基、卤代C1-C8烷氧基及一-(C1-C8烷基)氨基及二-(C1-C8烷基)氨基；R 1 is selected from hydrogen, halogen atom, hydroxyl, cyano, amino, C 1 -C 8 alkyl, halogenated C 1 -C 8 alkyl, C 1 -C 8 alkoxy, Halogenated C 1 -C 8 alkoxy and mono-(C 1 -C 8 alkyl)amino and di-(C 1 -C 8 alkyl)amino; R2为：(i)氢、卤原子、氰基或-COOH；R 2 is: (i) hydrogen, halogen atom, cyano group or -COOH; (ii)C1-C8烷酰基、C2-C8烷酮或C1-C8氨基甲酸根，其各自为未经取代或被1至9个分别选自Rb的取代基取代；或(ii) C 1 -C 8 alkanoyl, C 2 -C 8 alkanone or C 1 -C 8 carbamate, each of which is unsubstituted or substituted by 1 to 9 substituents respectively selected from R b ; or (iii)式-Rc-M-A-Ry基团，其中：(iii) a group of formula -Rc - MARy , wherein: Rc为C0-C3烷基；R c is C 0 -C 3 alkyl; M为键连接、N(Rz)、O、 S、SO2、-N(Rz)-、C(＝O)pN(Rz)、N(Rz)C(＝O)p、SO2N(Rz)或N(Rz)SO2，其中p为0或1；M is bonded, N(R z ), O, S, SO 2 , -N(R z )-, C(=O) p N(R z ), N(R z )C(=O) p , SO 2 N(R z ) or N(R z )SO 2 , where p is 0 or 1; A为键连接或C1-C8烷基，任选地被1至3个分别选自Rb的取代基取代；以及A is bonded or C 1 -C 8 alkyl, optionally substituted by 1 to 3 substituents selected from R b respectively; and Ry及Rz为： Ry and Rz are: (a)分别为氢、C1-C8烷基、C2-C8烯基、C2-C8炔基、C6-C10芳基C1-C8烷基、C2-C8烷基醚、C1-C8烷氧基、4元至10元碳环或杂环，或Ry及Rz接合至Rc而形成一个4元至10元碳环或杂环，其中各个Ry及Rz分别为未经取代或被1至9个分别选自Rb的取代基取代；或(a) hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 6 -C 10 aryl, C 1 -C 8 alkyl, C 2 -C 8 alkyl ethers, C 1 -C 8 alkoxy groups, 4-10-membered carbocyclic or heterocyclic rings, or R y and R z are joined to R c to form a 4- to 10-membered carbocyclic or heterocyclic rings, wherein each of Ry and Rz is unsubstituted or substituted with 1 to 9 substituents independently selected from Rb ; or (b)接合而形成一个4元至10元碳环或杂环，其为未经取代或被1至9个分别选自Rb的取代基取代；(b) joined to form a 4- to 10-membered carbocyclic or heterocyclic ring, which is unsubstituted or substituted by 1 to 9 substituents selected from R respectively; Ar1及Ar2分别是选自5元至10元芳香族碳环及杂环，其各自为未经取代或被1至3个分别选自式LRa群组的取代基取代；Ar 1 and Ar 2 are respectively selected from 5-membered to 10-membered aromatic carbocyclic rings and heterocyclic rings, each of which is unsubstituted or substituted by 1 to 3 substituents selected from the group of formula LRa ; L在各自出现时分别是选自键连接、-O-、-C(＝O)-、-OC(＝O)-、-C(＝O)O-、-O-C(＝O)O-、-S(O)M-、-NRx-、-C(＝O)NHRx-、-NHRxC(＝O)-、-NRxS(O)m-、S(O)mNRx-及-N[S(O)mRx]S(O)m-；其中m在各自出现时分别是选自0、1及2；以及Rx在各次出现时分别是选自氢及C1-C8烷基；L is selected from bond linkage, -O-, -C(=O)-, -OC(=O)-, -C(=O)O-, -OC(=O)O-, -OC(=O)O-, -S(O) M -, -NR x -, -C(=O)NHR x -, -NHR x C(=O)-, -NR x S(O) m -, S(O) m NR x - and -N[S(O) m R x ]S(O) m -; wherein m at each occurrence is selected from 0, 1 and 2; and R x at each occurrence is selected from hydrogen and C 1 -C 8 alkyl; Ra在各次出现时分别是选自：R a at each occurrence is selected from: (i)氢、卤原子、氰基及硝基；以及(i) hydrogen, halogen, cyano and nitro; and (ii)C1-C8烷基、C2-C8烯基、C2-C8炔基、C2-C8烷基醚、3元至10元杂环、一-(C1-C8烷基)氨基及二-(C1-C8烷基)氨基及(3元至10元杂环)C1-C6烷基，其各自为未经取代或被1至9个分别选自Rb的取代基取代；以及(ii) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 2 -C 8 alkyl ether, 3- to 10-membered heterocycle, one-(C 1 - C 8 alkyl) amino and di-(C 1 -C 8 alkyl) amino and (3-membered to 10-membered heterocycle) C 1 -C 6 alkyl, each of which is unsubstituted or replaced by 1 to 9, respectively is substituted with a substituent selected from R b ; and Rb在各次出现时分别是选自羟基、卤原子、氨基、氨基羰基、酰氨基、氰基、硝基、酮基、C1-C8烷基、C1-C8烷氧基、C1-C8烷硫基、C1-C8烷基醚、羟基C1-C8烷基、卤基C1-C8烷基、苯基、苯基(C1-C8烷基)、一-(C1-C6烷基)氨基及二-(C1-C6烷基)氨基、(SO2)C1-C8烷基、5元至7元杂环及(5元至7元杂环)(C1-C8烷基)；R b is selected from hydroxyl, halogen atom, amino, aminocarbonyl, amido, cyano, nitro, ketone, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 1 -C 8 alkyl ether, hydroxy C 1 -C 8 alkyl, halo C 1 -C 8 alkyl, phenyl, phenyl (C 1 -C 8 alkyl ), one-(C 1 -C 6 alkyl) amino and di-(C 1 -C 6 alkyl) amino, (SO 2 ) C 1 -C 8 alkyl, 5- to 7-membered heterocycle and (5 7-membered heterocycle) (C 1 -C 8 alkyl); 以及由由此降低辣椒辣素受体的钙传导。And by reducing the calcium conductance of capsaicin receptors thereby. 84.如权利要求83所述的方法，其中该化合物为如权利要求1、16、34或61中任一所述的化合物。84. The method of claim 83, wherein the compound is the compound of any one of claims 1, 16, 34 or 61. 85.如权利要求83所述的方法，其中该细胞为在动物体活体内接触的神经元细胞。85. The method of claim 83, wherein the cells are neuronal cells contacted in vivo in an animal body. 86.如权利要求85所述的方法，其中在接触期间该化合物是存在于动物的体液内。86. The method of claim 85, wherein the compound is present in the animal's body fluids during the contacting. 87.如权利要求86所述的方法，其中该化合物是以100nM或以下的浓度存在于动物血液中。87. The method of claim 86, wherein the compound is present in the blood of the animal at a concentration of 100 nM or less. 88.如权利要求85所述的方法，其中该动物为人类。88. The method of claim 85, wherein the animal is a human. 89.如权利要求85所述的方法，其中该化合物是口服给予。89. The method of claim 85, wherein the compound is administered orally. 90、一种抑制类香草配位子在试管内结合至辣椒辣素受体的方法，该方法包含辣椒辣素受体接触至少一种下式化合物或盐：90. A method of inhibiting the binding of vanilla-like ligands to capsaicin receptors in vitro, the method comprising contacting capsaicin receptors with at least one compound or salt of the following formula: 其中：in: V、X、W、Y及Z各自分别为N或CR1，其条件是V及X中的至少一个为N；V, X, W, Y and Z are each independently N or CR 1 with the proviso that at least one of V and X is N; U为N或CR2，但若V及X为N，则U为CR2；U is N or CR 2 , but if V and X are N, then U is CR 2 ; R1在各次出现时分别是选自氢、卤原子、羟基、氰基、氨基、C1-C8烷基、卤代C1-C8烷基、C1-C8烷氧基、卤代C1-C8烷氧基及一-(C1-C8烷基)氨基及二-(C1-C8烷基)氨基；R 1 is selected from hydrogen, halogen atom, hydroxyl, cyano, amino, C 1 -C 8 alkyl, halogenated C 1 -C 8 alkyl, C 1 -C 8 alkoxy, Halogenated C 1 -C 8 alkoxy and mono-(C 1 -C 8 alkyl)amino and di-(C 1 -C 8 alkyl)amino; R2为：(i)氢、卤原子、氰基或-COOH；R 2 is: (i) hydrogen, halogen atom, cyano group or -COOH; (ii)C1-C8烷酰基、C2-C8烷酮或C1-C8氨基甲酸根，其各自为未经取代或被1至9个分别选自Rb的取代基取代；或(ii) C 1 -C 8 alkanoyl, C 2 -C 8 alkanone or C 1 -C 8 carbamate, each of which is unsubstituted or substituted by 1 to 9 substituents respectively selected from R b ; or (iii)如式-Rc-M-A-Ry的基团，其中：(iii) A group of formula -Rc - MARy , wherein: Rc为C0-C3烷基；R c is C 0 -C 3 alkyl; M为键连接，N(Rz)、O、S、SO2、-N(Rz)-、C(＝O)pN(Rz)、N(Rz)C(＝O)p、SO2N(Rz)或N(Rz)SO2，其中p为0或1；M is a bond connection, N(R z ), O, S, SO 2 , -N(R z )-, C(=O) p N(R z ), N(R z )C(=O) p , SO 2 N(R z ) or N(R z )SO 2 , where p is 0 or 1; A为键连接或C1-C8烷基，任选地被1至3个分别选自Rb的取代基取代；以及A is bonded or C 1 -C 8 alkyl, optionally substituted by 1 to 3 substituents selected from R b respectively; and Ry及Rz为： Ry and Rz are: (a)分别为氢、C1-C8烷基、C2-C8烯基、C2-C8炔基、C6-C10芳基C1-C8烷基、C2-C8烷基醚、C1-C8烷氧基、4元至10元碳环或杂环，或Ry及Rz接合至Rc而形成一个4元至10元碳环或杂环，其中各个Ry及Rz分别为未经取代或被1至9个分别选自Rb的取代基取代；或(a) hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 6 -C 10 aryl, C 1 -C 8 alkyl, C 2 -C 8 alkyl ethers, C 1 -C 8 alkoxy groups, 4-10-membered carbocyclic or heterocyclic rings, or R y and R z are joined to R c to form a 4- to 10-membered carbocyclic or heterocyclic rings, wherein each of Ry and Rz is unsubstituted or substituted with 1 to 9 substituents independently selected from Rb ; or (b)接合而形成一个4元至10元碳环或杂环，其为未经取代或被1至9个分别选自Rb的取代基取代；(b) joined to form a 4- to 10-membered carbocyclic or heterocyclic ring, which is unsubstituted or substituted by 1 to 9 substituents selected from R respectively; Ar1及Ar2分别是选自5元至10元芳香族碳环及杂环，其各自为未经取代或被1至3个分别选自式LRa群组的取代基取代；Ar 1 and Ar 2 are respectively selected from 5-membered to 10-membered aromatic carbocyclic rings and heterocyclic rings, each of which is unsubstituted or substituted by 1 to 3 substituents selected from the group of formula LRa ; L在各自出现时分别是选自键连接、-O-、-C(＝O)-、-OC(＝O)-、-C(＝O)O-、-O-C(＝O)O-、-S(O)m-、-NRx-、-C(＝O)NHRx-、-NHRxC(＝O)-、-NRxS(O)m-、S(O)mNRx-及-N[S(O)mRx]S(O)m-；其中m在各自出现时分别是选自0、1及2；以及Rx在各次出现时分别是选自氢及C1-C8烷基；L is selected from bond linkage, -O-, -C(=O)-, -OC(=O)-, -C(=O)O-, -OC(=O)O-, -OC(=O)O-, -S(O) m -, -NR x -, -C(=O)NHR x -, -NHR x C(=O)-, -NR x S(O) m -, S(O) m NR x - and -N[S(O) m R x ]S(O) m -; wherein m at each occurrence is selected from 0, 1 and 2; and R x at each occurrence is selected from hydrogen and C 1 -C 8 alkyl; Ra在各次出现时分别是选自：R a at each occurrence is selected from: (i)氢、卤原子、氰基及硝基；以及(i) hydrogen, halogen, cyano and nitro; and (ii)C1-C8烷基、C2-C8烯基、C2-C8炔基、C2-C8烷基醚、3元至10元杂环、一-(C1-C8烷基)氨基及二-(C1-C8烷基)氨基及(3元至10元杂环)C1-C6烷基，其各自为未经取代或被1至9个分别选自Rb的取代基取代；以及(ii) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 2 -C 8 alkyl ether, 3- to 10-membered heterocycle, one-(C 1 - C 8 alkyl) amino and di-(C 1 -C 8 alkyl) amino and (3-membered to 10-membered heterocycle) C 1 -C 6 alkyl, each of which is unsubstituted or replaced by 1 to 9, respectively is substituted with a substituent selected from R b ; and Rb在各次出现时分别是选自羟基、卤原子、氨基、氨基羰基、酰氨基、氰基、硝基、酮基、C1-C8烷基、C1-C8烷氧基、C1-C8烷硫基、C1-C8烷基醚、羟基C1-C8烷基、卤基C1-C8烷基、苯基、苯基(C1-C8烷基)、一-(C1-C6烷基)氨基及二-(C1-C6烷基)氨基、(SO2)C1-C8烷基、5元至7元杂环及(5元至7元杂环)(C1-C8烷基)；R b is selected from hydroxyl, halogen atom, amino, aminocarbonyl, amido, cyano, nitro, ketone, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 1 -C 8 alkyl ether, hydroxy C 1 -C 8 alkyl, halo C 1 -C 8 alkyl, phenyl, phenyl (C 1 -C 8 alkyl ), one-(C 1 -C 6 alkyl) amino and di-(C 1 -C 6 alkyl) amino, (SO 2 ) C 1 -C 8 alkyl, 5- to 7-membered heterocycle and (5 7-membered heterocycle) (C 1 -C 8 alkyl); 其接触条件及用量是足够以可检测方式抑制类香草配位子结合至辣椒辣素受体。The contacting conditions and the amount are sufficient to detectably inhibit the binding of the vanilloid ligand to the capsaicin receptor. 91.如权利要求90所述的方法，其中该化合物为如权利要求1、16、34或61中任一所述的化合物。91. The method of claim 90, wherein the compound is the compound of any one of claims 1, 16, 34 or 61. 92、一种在患者体内抑制类香草配位子结合至辣椒辣素受体的方法，包含表达辣椒辣素受体的细胞接触下式化合物或盐：92. A method of inhibiting binding of a vanilloid ligand to a capsaicin receptor in a patient comprising contacting a cell expressing a capsaicin receptor with a compound or salt of the formula:
Figure A038024520061C1
Figure A038024520061C1
 其中：in: V、X、W、Y及Z各自分别为N或CR1，其条件是V及X中的至少一个为N；V, X, W, Y and Z are each independently N or CR 1 with the proviso that at least one of V and X is N; U为N或CR2，但若V及X为N，则U为CR2；U is N or CR 2 , but if V and X are N, then U is CR 2 ; R1在各次出现时分别是选自氢、卤原子、羟基、氰基、氨基、C1-C8烷基、卤代C1-C8烷基、C1-C8烷氧基、卤代C1-C8烷氧基及一-(C1-C8烷基)氨基及二-(C1-C8烷基)氨基；R 1 is selected from hydrogen, halogen atom, hydroxyl, cyano, amino, C 1 -C 8 alkyl, halogenated C 1 -C 8 alkyl, C 1 -C 8 alkoxy, Halogenated C 1 -C 8 alkoxy and mono-(C 1 -C 8 alkyl)amino and di-(C 1 -C 8 alkyl)amino; R2为：(i)氢、卤原子、氰基或-COOH；R 2 is: (i) hydrogen, halogen atom, cyano group or -COOH; (ii)C1-C8烷酰基、C2-C8烷酮或C1-C8氨基甲酸根，其各自为未经取代或被1至9个分别选自Rb的取代基取代；或(ii) C 1 -C 8 alkanoyl, C 2 -C 8 alkanone or C 1 -C 8 carbamate, each of which is unsubstituted or substituted by 1 to 9 substituents respectively selected from R b ; or (iii)如式-Rc-M-A-Ry的基团，其中：(iii) A group of formula -Rc - MARy , wherein: Rc为C0-C3烷基；R c is C 0 -C 3 alkyl; M为键连接、N(Rz)、O、S、SO2、-N(Rz)-、C(＝O)pN(Rz)、N(Rz)C(＝O)p、SO2N(Rz)或N(Rz)SO2，其中p为0或1；M is bonded, N(R z ), O, S, SO 2 , -N(R z )-, C(=O) p N(R z ), N(R z )C(=O) p , SO 2 N(R z ) or N(R z )SO 2 , where p is 0 or 1; A为键连接或C1-C8烷基，任选地被1至3个分别选自Rb的取代基取代；以及A is bonded or C 1 -C 8 alkyl, optionally substituted by 1 to 3 substituents selected from R b respectively; and Ry及Rz为： Ry and Rz are: (a)分别为氢、C1-C8烷基、C2-C8烯基、C2-C8炔基、C6-C10芳基C1-C8烷基、C2-C8烷基醚、C1-C8烷氧基、4元至10元碳环或杂环，或Ry及Rz接合至Rc而形成一个4元至10元碳环或杂环，其中各个Ry及Rz分别为未经取代或被1至9个分别选自Rb的取代基取代；或(a) hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 6 -C 10 aryl, C 1 -C 8 alkyl, C 2 -C 8 alkyl ethers, C 1 -C 8 alkoxy groups, 4-10-membered carbocyclic or heterocyclic rings, or R y and R z are joined to R c to form a 4- to 10-membered carbocyclic or heterocyclic rings, wherein each of Ry and Rz is unsubstituted or substituted with 1 to 9 substituents independently selected from Rb ; or (b)接合而形成一个4元至10元碳环或杂环，其为未经取代或被1至9个分别选自Rb的取代基取代；(b) joined to form a 4- to 10-membered carbocyclic or heterocyclic ring, which is unsubstituted or substituted by 1 to 9 substituents selected from R respectively; Ar1及Ar2分别是选自5元至10元芳香族碳环及杂环，其各自为未经取代或被1至3个分别选自式LRa群组的取代基取代；Ar 1 and Ar 2 are respectively selected from 5-membered to 10-membered aromatic carbocyclic rings and heterocyclic rings, each of which is unsubstituted or substituted by 1 to 3 substituents selected from the group of formula LRa ; L在各自出现时分别是选自键连接、-O-、-C(＝O)-、-OC(＝O)-、-C(＝O)O-、-O-C(＝O)O-、-S(O)m-、-NRx-、-C(＝O)NHRx-、-NHRxC(＝O)-、-NRxS(O)m-、S(O)mNRx-及-N[S(O)mRx]S(O)m-；其中m在各自出现时分别是选自0、1及2；以及Rx在各次出现时分别是选自氢及C1-C8烷基；L is selected from bond linkage, -O-, -C(=O)-, -OC(=O)-, -C(=O)O-, -OC(=O)O-, -OC(=O)O-, -S(O) m -, -NR x -, -C(=O)NHR x -, -NHR x C(=O)-, -NR x S(O) m -, S(O) m NR x - and -N[S(O) m R x ]S(O) m -; wherein m at each occurrence is selected from 0, 1 and 2; and R x at each occurrence is selected from hydrogen and C 1 -C 8 alkyl; Ra在各次出现时分别是选自：R a at each occurrence is selected from: (i)氢、卤原子、氰基及硝基；以及(i) hydrogen, halogen, cyano and nitro; and (ii)C1-C8烷基、C2-C8烯基、C2-C8炔基、C2-C8烷基醚、3元至10元杂环、一-(C1-C8烷基)氨基及二-(C1-C8烷基)氨基及(3元至10元杂环)C1-C6烷基，其各自为未经取代或被1至9个分别选自Rb的取代基取代；以及(ii) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 2 -C 8 alkyl ether, 3- to 10-membered heterocycle, one-(C 1 - C 8 alkyl) amino and di-(C 1 -C 8 alkyl) amino and (3-membered to 10-membered heterocycle) C 1 -C 6 alkyl, each of which is unsubstituted or replaced by 1 to 9, respectively is substituted with a substituent selected from R b ; and Rb在各次出现时分别是选自羟基、卤原子、氨基、氨基羰基、酰氨基、氰基、硝基、酮基、C1-C8烷基、C1-C8烷氧基、C1-C8烷硫基、C1-C8烷基醚、羟基C1-C8烷基、卤基C1-C8烷基、苯基、苯基(C1-C8烷基)、一-(C1-C6烷基)氨基及二-(C1-C6烷基)氨基、(SO2)C1-C8烷基、5元至7元杂环及(5元至7元杂环)(C1-C8烷基)；R b is selected from hydroxyl, halogen atom, amino, aminocarbonyl, amido, cyano, nitro, ketone, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 1 -C 8 alkyl ether, hydroxy C 1 -C 8 alkyl, halo C 1 -C 8 alkyl, phenyl, phenyl (C 1 -C 8 alkyl ), one-(C 1 -C 6 alkyl) amino and di-(C 1 -C 6 alkyl) amino, (SO 2 ) C 1 -C 8 alkyl, 5- to 7-membered heterocycle and (5 7-membered heterocycle) (C 1 -C 8 alkyl); 其用量是足够以可检测方式抑制类香草配位子在试管内结合至表达经克隆的辣椒辣素受体的细胞，由此在患者体内抑制类香草配位子结合至辣椒辣素受体。The amount is sufficient to detectably inhibit the binding of the vanilloid ligand to cells expressing the cloned capsaicin receptor in vitro, thereby inhibiting the binding of the vanilloid ligand to the capsaicin receptor in a patient. 93.如权利要求92所述的方法，其中该化合物为如权利要求1、16、34或61中任一所述的化合物。93. The method of claim 92, wherein the compound is the compound of any one of claims 1, 16, 34 or 61. 94.如权利要求92所述的方法，其中该患者为人类。94. The method of claim 92, wherein the patient is a human. 95.如权利要求92所述的方法，其中该化合物是以100nM或以下的浓度存在于动物血液。95. The method of claim 92, wherein the compound is present in the blood of the animal at a concentration of 100 nM or less. 96、一种治疗在患者体内对辣椒辣素受体调节有反应性的病情的方法，包含对该患者给予辣椒辣素受体调节用量的至少一种下式化合物或盐：96. A method of treating a condition responsive to capsaicin receptor modulation in a patient comprising administering to the patient a capsaicin receptor modulating amount of at least one compound or salt of the formula: 其中：in: V、X、W、Y及Z各自分别为N或CR1，其条件是V及X中的至少一个为N；V, X, W, Y and Z are each independently N or CR 1 with the proviso that at least one of V and X is N; U为N或CR2，但若V及X为N，则U为CR2；U is N or CR 2 , but if V and X are N, then U is CR 2 ; R1在各次出现时分别是选自氢、卤原子、羟基、氰基、氨基、C1-C8烷基、卤代C1-C8烷基、C1-C8烷氧基、卤代C1-C8烷氧基及一-(C1-C8烷基)氨基及二-(C1-C8烷基)氨基；R 1 is selected from hydrogen, halogen atom, hydroxyl, cyano, amino, C 1 -C 8 alkyl, halogenated C 1 -C 8 alkyl, C 1 -C 8 alkoxy, Halogenated C 1 -C 8 alkoxy and mono-(C 1 -C 8 alkyl)amino and di-(C 1 -C 8 alkyl)amino; R2为：(i)氢、卤原子、氰基或-COOH；R 2 is: (i) hydrogen, halogen atom, cyano group or -COOH; (ii)C1-C8烷酰基、C2-C8烷酮或C1-C8氨基甲酸根，其各自为未经取代或被1至9个分别选自Rb的取代基取代；或(ii) C 1 -C 8 alkanoyl, C 2 -C 8 alkanone or C 1 -C 8 carbamate, each of which is unsubstituted or substituted by 1 to 9 substituents respectively selected from R b ; or (iii)如式-Rc-M-A-Ry的基团，其中：(iii) A group of formula -Rc - MARy , wherein: Rc为C0-C3烷基；R c is C 0 -C 3 alkyl; M为键连接，N(Rz)、O、S、SO2、-N(Rz)-、C(＝O)pN(Rz)、N(Rz)C(＝O)p、SO2N(Rz)或N(Rz)SO2，其中p为0或1；M is a bond connection, N(R z ), O, S, SO 2 , -N(R z )-, C(=O) p N(R z ), N(R z )C(=O) p , SO 2 N(R z ) or N(R z )SO 2 , where p is 0 or 1; A为键连接或C1-C8烷基，任选地被1至3个分别选自Rb的取代基取代；以及A is bonded or C 1 -C 8 alkyl, optionally substituted by 1 to 3 substituents selected from R b respectively; and Ry及Rz为： Ry and Rz are: (a)分别为氢、C1-C8烷基、C2-C8烯基、C2-C8炔基、C6-C10芳基C1-C8烷基、C2-C8烷基醚、C1-C8烷氧基、4元至10元碳环或杂环，或Ry及Rz接合至Rc而形成一个4元至10元碳环或杂环，其中各个Ry及Rz分别为未经取代或被1至9个分别选自Rb的取代基取代；或(a) hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 6 -C 10 aryl, C 1 -C 8 alkyl, C 2 -C 8 alkyl ethers, C 1 -C 8 alkoxy groups, 4-10-membered carbocyclic or heterocyclic rings, or R y and R z are joined to R c to form a 4- to 10-membered carbocyclic or heterocyclic rings, wherein each of Ry and Rz is unsubstituted or substituted with 1 to 9 substituents independently selected from Rb ; or (b)接合而形成一个4元至10元碳环或杂环，其为未经取代或被1至9个分别选自Rb的取代基取代；(b) joined to form a 4- to 10-membered carbocyclic or heterocyclic ring, which is unsubstituted or substituted by 1 to 9 substituents selected from R respectively; Ar1及Ar2分别是选自5元至10元芳香族碳环及杂环，其各自为未经取代或被1至3个分别选自式LRa群组的取代基取代；Ar 1 and Ar 2 are respectively selected from 5-membered to 10-membered aromatic carbocyclic rings and heterocyclic rings, each of which is unsubstituted or substituted by 1 to 3 substituents selected from the group of formula LRa ; L在各自出现时分别是选自键连接、-O-、-C(＝O)-、-OC(＝O)-、-C(＝O)O-、-O-C(＝O)O-、-S(O)m-、-NRx-、-C(＝O)NHRx-、-NHRxC(＝O)-、-NRxS(O)m-、S(O)mNRx-及-N[S(O)mRx]S(O)m-；其中m在各自出现时分别是选自0、1及2；以及Rx在各次出现时分别是选自氢及C1-C8烷基；L is selected from bond linkage, -O-, -C(=O)-, -OC(=O)-, -C(=O)O-, -OC(=O)O-, -OC(=O)O-, -S(O) m -, -NR x -, -C(=O)NHR x -, -NHR x C(=O)-, -NR x S(O) m -, S(O) m NR x - and -N[S(O) m R x ]S(O) m -; wherein m at each occurrence is selected from 0, 1 and 2; and R x at each occurrence is selected from hydrogen and C 1 -C 8 alkyl; Ra在各次出现时分别是选自：R a at each occurrence is selected from: (i)氢、卤原子、氰基及硝基；以及(i) hydrogen, halogen, cyano and nitro; and (ii)C1-C8烷基、C2-C8烯基、C2-C8炔基、C2-C8烷基醚、3元至10元杂环、一-(C1-C8烷基)氨基及二-(C1-C8烷基)氨基及(3元至10元杂环)C1-C6烷基，其各自为未经取代或被1至9个分别选自Rb的取代基取代；以及(ii) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 2 -C 8 alkyl ether, 3- to 10-membered heterocycle, one-(C 1 - C 8 alkyl) amino and di-(C 1 -C 8 alkyl) amino and (3-membered to 10-membered heterocycle) C 1 -C 6 alkyl, each of which is unsubstituted or replaced by 1 to 9, respectively is substituted with a substituent selected from R b ; and Rb在各次出现时分别是选自羟基、卤原子、氨基、氨基羰基、酰氨基、氰基、硝基、酮基、C1-C8烷基、C1-C8烷氧基、C1-C8烷硫基、C1-C8烷基醚、羟基C1-C8烷基、卤基C1-C8烷基、苯基、苯基(C1-C8烷基)、一-(C1-C6烷基)氨基及二-(C1-C6烷基)氨基、(SO2)C1-C8烷基、5元至7元杂环及(5元至7元杂环)(C1-C8烷基)；R b is selected from hydroxyl, halogen atom, amino, aminocarbonyl, amido, cyano, nitro, keto, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 1 -C 8 alkyl ether, hydroxy C 1 -C 8 alkyl, halo C 1 -C 8 alkyl, phenyl, phenyl (C 1 -C 8 alkyl ), one-(C 1 -C 6 alkyl) amino and di-(C 1 -C 6 alkyl) amino, (SO 2 ) C 1 -C 8 alkyl, 5- to 7-membered heterocycle and (5 7-membered heterocycle) (C 1 -C 8 alkyl); 以及由此缓解患者的病情。and relieve the patient's condition. 97.如权利要求96所述的方法，其中该化合物为如权利要求1、16、34或61中任一所述的化合物。97. The method of claim 96, wherein the compound is the compound of any one of claims 1, 16, 34 or 61. 98.如权利要求96所述的方法，其中该患者患有(i)暴露于辣椒辣素，(ii)因暴露于热而产生的烧烫伤或刺激，(iii)因暴露于光而产生的烧烫伤或刺激，(iv)因暴露于催泪瓦斯、空气污染或胡椒喷雾剂而产生的烧烫伤、支气管缩窄或刺激，或(v)因暴露于酸而产生的烧烫伤或刺激。98. The method of claim 96, wherein the patient suffers from (i) exposure to capsaicin, (ii) burns or irritation from exposure to heat, (iii) burns or irritation from exposure to light Burns or irritation, (iv) burns, bronchoconstriction or irritation from exposure to tear gas, air pollution, or pepper spray, or (v) burns or irritation from acid exposure. 99.如权利要求96所述的方法，其中该化合物是以100nM或以下的浓度存在于动物血液。99. The method of claim 96, wherein the compound is present in the blood of the animal at a concentration of 100 nM or less. 100.如权利要求96所述的方法，其中该治疗病情是治疗气喘或慢性阻塞性肺疾。100. The method of claim 96, wherein the treating condition is treating asthma or chronic obstructive pulmonary disease. 101、一种治疗患者疼痛的方法，包含对患有疼痛的患者给予辣椒辣素受体调节用量的至少一种下式化合物或盐：101. A method of treating pain in a patient comprising administering to a patient suffering from pain a capsaicin receptor modulating amount of at least one compound or salt of the formula: 其中：in: V、X、W、Y及Z各自分别为N或CR1，其条件是V及X中的至少一个为N；V, X, W, Y and Z are each independently N or CR 1 with the proviso that at least one of V and X is N; U为N或CR2，但若V及X为N，则U为CR2；U is N or CR 2 , but if V and X are N, then U is CR 2 ; R1在各次出现时分别是选自氢、卤原子、羟基、氰基、氨基、C1-C8烷基、卤代C1-C8烷基、C1-C8烷氧基、卤代C1-C8烷氧基及一-(C1-C8烷基)氨基及二-(C1-C8烷基)氨基；R 1 is selected from hydrogen, halogen atom, hydroxyl, cyano, amino, C 1 -C 8 alkyl, halogenated C 1 -C 8 alkyl, C 1 -C 8 alkoxy, Halogenated C 1 -C 8 alkoxy and mono-(C 1 -C 8 alkyl)amino and di-(C 1 -C 8 alkyl)amino; R2为：(i)氢、卤原子、氰基或-COOH；R 2 is: (i) hydrogen, halogen atom, cyano group or -COOH; (ii)C1-C8烷酰基、C2-C8烷酮或C1-C8氨基甲酸根，其各自为未经取代或被1至9个分别选自Rb的取代基取代；或(ii) C 1 -C 8 alkanoyl, C 2 -C 8 alkanone or C 1 -C 8 carbamate, each of which is unsubstituted or substituted by 1 to 9 substituents respectively selected from R b ; or (iii)如式-Rc-M-A-Ry的基团，其中：(iii) A group of formula -Rc - MARy , wherein: Rc为C0-C3烷基；R c is C 0 -C 3 alkyl; M为键连接、N(Rz)、O、S、SO2、-N(Rz)-、C(＝O)pN(Rz)、N(Rz)C(＝O)p、SO2N(Rz)或N(Rz)SO2，其中p为0或1；M is bonded, N(R z ), O, S, SO 2 , -N(R z )-, C(=O) p N(R z ), N(R z )C(=O) p , SO 2 N(R z ) or N(R z )SO 2 , where p is 0 or 1; A为键连接或C1-C8烷基，任选地被1至3个分别选自Rb的取代基取代；以及A is bonded or C 1 -C 8 alkyl, optionally substituted by 1 to 3 substituents selected from R b respectively; and Ry及Rz为： Ry and Rz are: (a)分别为氢、C1-C8烷基、C2-C8烯基、C2-C8炔基、C6-C10芳基C1-C8烷基、C2-C8烷基醚、C1-C8烷氧基、4元至10元碳环或杂环，或Ry及Rz接合至Rc而形成一个4元至10元碳环或杂环，其中各个Ry及Rz分别为未经取代或被1至9个分别选自Rb的取代基取代；或(a) hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 6 -C 10 aryl, C 1 -C 8 alkyl, C 2 -C 8 alkyl ethers, C 1 -C 8 alkoxy groups, 4-10-membered carbocyclic or heterocyclic rings, or R y and R z are joined to R c to form a 4- to 10-membered carbocyclic or heterocyclic rings, wherein each of Ry and Rz is unsubstituted or substituted with 1 to 9 substituents independently selected from Rb ; or (b)接合而形成一个4元至10元碳环或杂环，其为未经取代或被1至9个分别选自Rb的取代基取代；(b) joined to form a 4- to 10-membered carbocyclic or heterocyclic ring, which is unsubstituted or substituted by 1 to 9 substituents selected from R respectively; Ar1及Ar2分别是选自5元至10元芳香族碳环及杂环，其各自为未经取代或被1至3个分别选自式LRa群组的取代基取代；Ar 1 and Ar 2 are respectively selected from 5-membered to 10-membered aromatic carbocyclic rings and heterocyclic rings, each of which is unsubstituted or substituted by 1 to 3 substituents selected from the group of formula LRa ; L在各自出现时分别是选自键连接、-O-、-C(＝O)-、-OC(＝O)-、-C(＝O)O-、-O-C(＝O)O-、-S(O)m-、-NRx-、-C(＝O)NHRx-、-NHRxC(＝O)-、-NRxS(O)m-、S(O)mNRx-及-N[S(O)mRx]S(O)m-；其中m在各自出现时分别是选自0、1及2；以及Rx在各次出现时分别是选自氢及C1-C8烷基；L is selected from bond linkage, -O-, -C(=O)-, -OC(=O)-, -C(=O)O-, -OC(=O)O-, -OC(=O)O-, -S(O) m -, -NR x -, -C(=O)NHR x -, -NHR x C(=O)-, -NR x S(O) m -, S(O) m NR x - and -N[S(O) m R x ]S(O) m -; wherein m at each occurrence is selected from 0, 1 and 2; and R x at each occurrence is selected from hydrogen and C 1 -C 8 alkyl; Ra在各次出现时分别是选自：R a at each occurrence is selected from: (i)氢、卤原子、氰基及硝基；以及(i) hydrogen, halogen, cyano and nitro; and (ii)C1-C8烷基、C2-C8烯基、C2-C8炔基、C2-C8烷基醚、3元至10元杂环、一-(C1-C8烷基)氨基及二-(C1-C8烷基)氨基及(3元至10元杂环)C1-C6烷基，其各自为未经取代或被1至9个分别选自Rb的取代基取代；以及(ii) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 2 -C 8 alkyl ether, 3- to 10-membered heterocycle, one-(C 1 - C 8 alkyl) amino and di-(C 1 -C 8 alkyl) amino and (3-membered to 10-membered heterocycle) C 1 -C 6 alkyl, each of which is unsubstituted or replaced by 1 to 9, respectively is substituted with a substituent selected from R b ; and Rb在各次出现时分别是选自羟基、卤原子、氨基、氨基羰基、酰氨基、氰基、硝基、酮基、C1-C8烷基、C1-C8烷氧基、C1-C8烷硫基、C1-C8烷基醚、羟基C1-C8烷基、卤基C1-C8烷基、苯基、苯基(C1-C8烷基)、一-(C1-C6烷基)氨基及二-(C1-C6烷基)氨基、(SO2)C1-C8烷基、5元至7元杂环及(5元至7元杂环)(C1-C8烷基)；R b is selected from hydroxyl, halogen atom, amino, aminocarbonyl, amido, cyano, nitro, ketone, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 1 -C 8 alkyl ether, hydroxy C 1 -C 8 alkyl, halo C 1 -C 8 alkyl, phenyl, phenyl (C 1 -C 8 alkyl ), one-(C 1 -C 6 alkyl) amino and di-(C 1 -C 6 alkyl) amino, (SO 2 ) C 1 -C 8 alkyl, 5- to 7-membered heterocycle and (5 7-membered heterocycle) (C 1 -C 8 alkyl); 以及由此缓解患者的疼痛。and relieve the patient's pain. 102.如权利要求101所述的方法，其中该化合物为如权利要求1、16、34或61中任一所述的化合物。102. The method of claim 101, wherein the compound is the compound of any one of claims 1, 16, 34 or 61. 103.如权利要求101所述的方法，其中该化合物是以100nM或以下的浓度存在于动物血液。103. The method of claim 101, wherein the compound is present in the blood of the animal at a concentration of 100 nM or less. 104.如权利要求101所述的方法，其中该患者患有神经病变疼痛。104. The method of claim 101, wherein the patient suffers from neuropathic pain. 105.如权利要求101所述的方法，其中该疼痛是与一种选自下列的病情相关：乳房切除术后疼痛综合征、残肢痛、假性肢痛、口腔神经病变疼痛、牙痛、疱疹后神经痛、糖尿病性神经病变、反射交感神经营养失调、三叉神经痛、骨关结炎、类风湿性关节炎、神经肌痛、吉蓝巴尔综合征、感觉异常性股痛、烧伤-口腔综合征、两侧周边神经病变、灼痛、神经细胞炎、神经痛、艾滋病相关神经病变、MS相关神经病变、脊柱受伤相关疼痛、手术相关疼痛、肌肉骨骼痛、背痛、头痛、偏头痛、心绞痛、分娩痛、痔疮痛、消化不良痛、夏科氏氏疼痛、肠胀气痛、经痛、癌症痛、暴露于蛇毒、激躁性肠综合征、发炎性肠病及/或怆伤。105. The method of claim 101, wherein the pain is associated with a condition selected from the group consisting of post-mastectomy pain syndrome, stump pain, pseudolimb pain, oral neuropathy pain, toothache, herpes Posterior Neuralgia, Diabetic Neuropathy, Reflex Sympathetic Dystrophy, Trigeminal Neuralgia, Osteoarthritis, Rheumatoid Arthritis, Neuromyalgia, Guillambard Syndrome, Paresthesia Gastrogia, Burn-Oral Syndrome Bilateral peripheral neuropathy, burning pain, neurocytitis, neuralgia, AIDS-related neuropathy, MS-related neuropathy, spinal injury-related pain, surgery-related pain, musculoskeletal pain, back pain, headache, migraine, angina , labor pain, hemorrhoid pain, indigestion pain, Charcot pain, flatulence pain, menstrual pain, cancer pain, exposure to snake venom, irritable bowel syndrome, inflammatory bowel disease and/or trauma. 106.如权利要求101所述的方法，其中所述患者为人类。106. The method of claim 101, wherein the patient is a human. 107、一种治疗患者搔痒的方法，包含对该患者给予辣椒辣素受体调节用量的下式化合物或盐：107. A method of treating itching in a patient, comprising administering to the patient a capsaicin receptor modulating amount of a compound or salt of the formula:
Figure A038024520068C1
Figure A038024520068C1
 其中：in: V、X、W、Y及Z各自分别为N或CR1，其条件是V及X中的至少一个为N；V, X, W, Y and Z are each independently N or CR 1 with the proviso that at least one of V and X is N; U为N或CR2，但若V及X为N，则U为CR2；U is N or CR 2 , but if V and X are N, then U is CR 2 ; R1在各次出现时分别是选自氢、卤原子、羟基、氰基、氨基、C1-C8烷基、卤代C1-C8烷基、C1-C8烷氧基、卤代C1-C8烷氧基及一-(C1-C8烷基)氨基及二-(C1-C8烷基)氨基；R 1 is selected from hydrogen, halogen atom, hydroxyl, cyano, amino, C 1 -C 8 alkyl, halogenated C 1 -C 8 alkyl, C 1 -C 8 alkoxy, Halogenated C 1 -C 8 alkoxy and mono-(C 1 -C 8 alkyl)amino and di-(C 1 -C 8 alkyl)amino; R2为：(i)氢、卤原子、氰基或-COOH；R 2 is: (i) hydrogen, halogen atom, cyano group or -COOH; (ii)C1-C8烷酰基、C2-C8烷酮或C1-C8氨基甲酸根，其各自为未经取代或被1至9个分别选自Rb的取代基取代；或(ii) C 1 -C 8 alkanoyl, C 2 -C 8 alkanone or C 1 -C 8 carbamate, each of which is unsubstituted or substituted by 1 to 9 substituents respectively selected from R b ; or (iii)如式-Rc-M-A-Ry的基团，其中：(iii) A group of formula -Rc - MARy , wherein: Rc为C0-C3烷基；R c is C 0 -C 3 alkyl; M为键连接、N(Rz)、O、S、SO2、-N(Rz)-、C(＝O)pN(Rz)、N(Rz)C(＝O)p、SO2N(Rz)或N(Rz)SO2，其中p为0或1；M is bonded, N(R z ), O, S, SO 2 , -N(R z )-, C(=O) p N(R z ), N(R z )C(=O) p , SO 2 N(R z ) or N(R z )SO 2 , where p is 0 or 1; A为键连接或C1-C8烷基，任选地被1至3个分别选自Rb的取代基取代；以及A is bonded or C 1 -C 8 alkyl, optionally substituted by 1 to 3 substituents selected from R b respectively; and Ry及Rz为： Ry and Rz are: (a)分别为氢、C1-C8烷基、C2-C8烯基、C2-C8炔基、C6-C10芳基C1-C8烷基、C2-C8烷基醚、C1-C8烷氧基、4元至10元碳环或杂环，或接合至Rc而形成一个4元至10元碳环或杂环，其中各个Ry及Rz分别为未经取代或被1至9个分别选自Rb的取代基取代；或(a) hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 6 -C 10 aryl, C 1 -C 8 alkyl, C 2 -C 8 alkyl ether, C 1 -C 8 alkoxy, 4 to 10 membered carbocyclic or heterocyclic ring, or joined to R c to form a 4 to 10 membered carbocyclic or heterocyclic ring, wherein each of R y and R z are each unsubstituted or substituted by 1 to 9 substituents respectively selected from R b ; or (b)接合而形成一个4元至10元碳环或杂环，其为未经取代或被1至9个分别选自Rb的取代基取代；(b) joined to form a 4- to 10-membered carbocyclic or heterocyclic ring, which is unsubstituted or substituted by 1 to 9 substituents selected from R respectively; Ar1及Ar2分别是选自5元至10元芳香族碳环及杂环，其各自为未经取代或被1至3个分别选自式LRa群组的取代基取代；Ar 1 and Ar 2 are respectively selected from 5-membered to 10-membered aromatic carbocyclic rings and heterocyclic rings, each of which is unsubstituted or substituted by 1 to 3 substituents selected from the group of formula LRa ; L在各自出现时分别是选自键连接、-O-、-C(＝O)-、-OC(＝O)-、-C(＝O)O-、-O-C(＝O)O-、-S(O)m-、-NRx-、-C(＝O)NHRx-、-NHRxC(＝O)-、-NRxS(O)m-、S(O)mNRx-及-N[S(O)mRx]S(O)m-；其中m在各自出现时分别是选自0、1及2；以及Rx在各次出现时分别是选自氢及C1-C8烷基；L is selected from bond linkage, -O-, -C(=O)-, -OC(=O)-, -C(=O)O-, -OC(=O)O-, -OC(=O)O-, -S(O) m -, -NR x -, -C(=O)NHR x -, -NHR x C(=O)-, -NR x S(O) m -, S(O) m NR x - and -N[S(O) m R x ]S(O) m -; wherein m at each occurrence is selected from 0, 1 and 2; and R x at each occurrence is selected from hydrogen and C 1 -C 8 alkyl; Ra在各次出现时分别是选自：R a at each occurrence is selected from: (i)氢、卤原子、氰基及硝基；以及(i) hydrogen, halogen, cyano and nitro; and (ii)C1-C8烷基、C2-C8烯基、C2-C8炔基、C2-C8烷基醚、3元至10元杂环、一-(C1-C8烷基)氨基及二-(C1-C8烷基)氨基及(3元至10元杂环)C1-C6烷基，其各自为未经取代或被1至9个分别选自Rb的取代基取代；以及(ii) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 2 -C 8 alkyl ether, 3- to 10-membered heterocycle, one-(C 1 - C 8 alkyl) amino and di-(C 1 -C 8 alkyl) amino and (3-membered to 10-membered heterocycle) C 1 -C 6 alkyl, each of which is unsubstituted or replaced by 1 to 9, respectively is substituted with a substituent selected from R b ; and Rb在各次出现时分别是选自羟基、卤原子、氨基、氨基羰基、酰氨基、氰基、硝基、酮基、C1-C8烷基、C1-C8烷氧基、C1-C8烷硫基、C1-C8烷基醚、羟基C1-C8烷基、卤基C1-C8烷基、苯基、苯基(C1-C8烷基)、一-(C1-C6烷基)氨基及二-(C1-C6烷基)氨基、(SO2)C1-C8烷基、5元至7元杂环及(5元至7元杂环)(C1-C8烷基)；R b is selected from hydroxyl, halogen atom, amino, aminocarbonyl, amido, cyano, nitro, ketone, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 1 -C 8 alkyl ether, hydroxy C 1 -C 8 alkyl, halo C 1 -C 8 alkyl, phenyl, phenyl (C 1 -C 8 alkyl ), one-(C 1 -C 6 alkyl) amino and di-(C 1 -C 6 alkyl) amino, (SO 2 ) C 1 -C 8 alkyl, 5- to 7-membered heterocycle and (5 7-membered heterocycle) (C 1 -C 8 alkyl); 以及由此缓解患者的搔痒。And thereby relieve the patient's itching. 108.如权利要求107所述的方法，其中该化合物为如权利要求1、16、34或61中任一所述的化合物。108. The method of claim 107, wherein the compound is the compound of any one of claims 1, 16, 34 or 61. 109、一种治疗患者咳嗽或打嗝的方法，包含对该患者给予辣椒辣素受体调节用量的下式化合物或盐：109. A method of treating cough or hiccup in a patient comprising administering to the patient a capsaicin receptor modulating amount of a compound or salt of the formula:
Figure A038024520069C1
Figure A038024520069C1
 其中：in: V、X、W、Y及Z各自分别为N或CR1，其条件是V及X中的至少一个为N；V, X, W, Y and Z are each independently N or CR 1 with the proviso that at least one of V and X is N; U为N或CR2，但若V及X为N，则U为CR2；U is N or CR 2 , but if V and X are N, then U is CR 2 ; R1在各次出现时分别是选自氢、卤原子、羟基、氰基、氨基、C1-C8烷基、卤代C1-C8烷基、C1-C8烷氧基、卤代C1-C8烷氧基及一-(C1-C8烷基)氨基及二-(C1-C8烷基)氨基；R 1 is selected from hydrogen, halogen atom, hydroxyl, cyano, amino, C 1 -C 8 alkyl, halogenated C 1 -C 8 alkyl, C 1 -C 8 alkoxy, Halogenated C 1 -C 8 alkoxy and mono-(C 1 -C 8 alkyl)amino and di-(C 1 -C 8 alkyl)amino; R2为：(i)氢、卤原子、氰基或-COOH；R 2 is: (i) hydrogen, halogen atom, cyano group or -COOH; (ii)C1-C8烷酰基、C2-C8烷酮或C1-C8氨基甲酸根，其各自为未经取代或被1至9个分别选自Rb的取代基取代；或(ii) C 1 -C 8 alkanoyl, C 2 -C 8 alkanone or C 1 -C 8 carbamate, each of which is unsubstituted or substituted by 1 to 9 substituents respectively selected from R b ; or (iii)如式-Rc-M-A-Ry的基团，其中：(iii) A group of formula -Rc - MARy , wherein: Rc为C0-C3烷基；R c is C 0 -C 3 alkyl; M为键连接、N(Rz)、O、S、SO2、-N(Rz)-、C(＝O)pN(Rz)、N(Rz)C(＝O)p、SO2N(Rz)或N(Rz)SO2，其中p为0或1；M is bonded, N(R z ), O, S, SO 2 , -N(R z )-, C(=O) p N(R z ), N(R z )C(=O) p , SO 2 N(R z ) or N(R z )SO 2 , where p is 0 or 1; A为键连接或C1-C8烷基，任选地被1至3个分别选自Rb的取代基取代；以及A is bonded or C 1 -C 8 alkyl, optionally substituted by 1 to 3 substituents selected from R b respectively; and Ry及Rz为： Ry and Rz are: (a)分别为氢、C1-C8烷基、C2-C8烯基、C2-C8炔基、C6-C10芳基C1-C8烷基、C2-C8烷基醚、C1-C8烷氧基、4元至10元碳环或杂环，或接合至Rc而形成一个4元至10元碳环或杂环，其中各个Ry及Rz分别为未经取代或被1至9个分别选自Rb的取代基取代；或(a) hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 6 -C 10 aryl, C 1 -C 8 alkyl, C 2 -C 8 alkyl ether, C 1 -C 8 alkoxy, 4 to 10 membered carbocyclic or heterocyclic ring, or joined to R c to form a 4 to 10 membered carbocyclic or heterocyclic ring, wherein each of R y and R z are each unsubstituted or substituted by 1 to 9 substituents respectively selected from R b ; or (b)接合而形成一个4元至10元碳环或杂环，其为未经取代或被1至9个分别选自Rb的取代基取代；(b) joined to form a 4- to 10-membered carbocyclic or heterocyclic ring, which is unsubstituted or substituted by 1 to 9 substituents selected from R respectively; Ar1及Ar2分别是选自5元至10元芳香族碳环及杂环，其各自为未经取代或被1至3个分别选自式LRa群组的取代基取代；Ar 1 and Ar 2 are respectively selected from 5-membered to 10-membered aromatic carbocyclic rings and heterocyclic rings, each of which is unsubstituted or substituted by 1 to 3 substituents selected from the group of formula LRa ; L在各自出现时分别是选自键连接、-O-、-C(＝O)-、-OC(＝O)-、-C(＝O)O-、-O-C(＝O)O-、-S(O)m-、-NRx-、-C(＝O)NHRx-、-NHRxC(＝O)-、-NRxS(O)m-、S(O)mNRx-及-N[S(O)mRx]S(O)m-；其中m在各自出现时分别是选自0、1及2；以及Rx在各次出现时分别是选自氢及C1-C8烷基；L is selected from bond linkage, -O-, -C(=O)-, -OC(=O)-, -C(=O)O-, -OC(=O)O-, -OC(=O)O-, -S(O) m -, -NR x -, -C(=O)NHR x -, -NHR x C(=O)-, -NR x S(O) m -, S(O) m NR x - and -N[S(O) m R x ]S(O) m -; wherein m at each occurrence is selected from 0, 1 and 2; and R x at each occurrence is selected from hydrogen and C 1 -C 8 alkyl; Ra在各次出现时分别是选自：R a at each occurrence is selected from: (i)氢、卤原子、氰基及硝基；以及(i) hydrogen, halogen, cyano and nitro; and (ii)C1-C8烷基、C2-C8烯基、C2-C8炔基、C2-C8烷基醚、3元至10元杂环、一-(C1-C8烷基)氨基及二-(C1-C8烷基)氨基及(3元至10元杂环)C1-C6烷基，其各自为未经取代或被1至9个分别选自Rb的取代基取代；以及(ii) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 2 -C 8 alkyl ether, 3- to 10-membered heterocycle, one-(C 1 - C 8 alkyl) amino and di-(C 1 -C 8 alkyl) amino and (3-membered to 10-membered heterocycle) C 1 -C 6 alkyl, each of which is unsubstituted or replaced by 1 to 9, respectively is substituted with a substituent selected from R b ; and Rb在各次出现时分别是选自羟基、卤原子、氨基、氨基羰基、酰氨基、氰基、硝基、酮基、C1-C8烷基、C1-C8烷氧基、C1-C8烷硫基、C1-C8烷基醚、羟基C1-C8烷基、卤基C1-C8烷基、苯基、苯基(C1-C8烷基)、一-(C1-C6烷基)氨基及二-(C1-C6烷基)氨基、(SO2)C1-C8烷基、5元至7元杂环及(5元至7元杂环)(C1-C8烷基)；以及由此缓解患者的咳嗽或打嗝。R b is selected from hydroxyl, halogen atom, amino, aminocarbonyl, amido, cyano, nitro, ketone, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 1 -C 8 alkyl ether, hydroxy C 1 -C 8 alkyl, halo C 1 -C 8 alkyl, phenyl, phenyl (C 1 -C 8 alkyl ), one-(C 1 -C 6 alkyl) amino and di-(C 1 -C 6 alkyl) amino, (SO 2 ) C 1 -C 8 alkyl, 5- to 7-membered heterocycle and (5 to 7-membered heterocycle) (C 1 -C 8 alkyl); and thereby relieve coughing or hiccupping in the patient. 110.如权利要求109所述的方法，其中该化合物为如权利要求1、16、34或61中任一所述的化合物。110. The method of claim 109, wherein the compound is the compound of any one of claims 1, 16, 34, or 61. 111、一种促进肥胖患者体重减轻的方法，包含对该患者给予辣椒辣素受体调节用量的下式化合物或盐：111. A method of promoting weight loss in an obese patient, comprising administering to the patient a capsaicin receptor modulating amount of a compound or salt of the following formula:
Figure A038024520071C1
Figure A038024520071C1
 其中：in: V、X、W、Y及Z各自分别为N或CR1，但V及X中的至少一个为N；each of V, X, W, Y and Z is N or CR 1 , but at least one of V and X is N; U为N或CR2，但若V及X为N，则U为CR2；U is N or CR 2 , but if V and X are N, then U is CR 2 ; R1在各次出现时分别是选自氢、卤原子、羟基、氰基、氨基、C1-C8烷基、卤代C1-C8烷基、C1-C8烷氧基、卤代C1-C8烷氧基及一-(C1-C8烷基)氨基及二-(C1-C8烷基)氨基；R 1 is selected from hydrogen, halogen atom, hydroxyl, cyano, amino, C 1 -C 8 alkyl, halogenated C 1 -C 8 alkyl, C 1 -C 8 alkoxy, Halogenated C 1 -C 8 alkoxy and mono-(C 1 -C 8 alkyl)amino and di-(C 1 -C 8 alkyl)amino; R2为：(i)氢、卤原子、氰基或-COOH；R 2 is: (i) hydrogen, halogen atom, cyano group or -COOH; (ii)C1-C8烷酰基、C2-C8烷酮或C1-C8氨基甲酸根，其各自为未经取代或被1至9个分别选自Rb的取代基取代；或(ii) C 1 -C 8 alkanoyl, C 2 -C 8 alkanone or C 1 -C 8 carbamate, each of which is unsubstituted or substituted by 1 to 9 substituents respectively selected from R b ; or (iii)如式-Rc-M-A-Ry的基团，其中：(iii) A group of formula -Rc - MARy , wherein: Rc为C0-C3烷基；R c is C 0 -C 3 alkyl; M为键连接、N(Rz)、O、S、SO2、-N(Rz)-、C(＝O)pN(Rz)、N(Rz)C(＝O)p、SO2N(Rz)或N(Rz)SO2，其中p为0或1；M is bonded, N(R z ), O, S, SO 2 , -N(R z )-, C(=O) p N(R z ), N(R z )C(=O) p , SO 2 N(R z ) or N(R z )SO 2 , where p is 0 or 1; A为键连接或C1-C8烷基，任选地被1至3个分别选自Rb的取代基取代；以及A is bonded or C 1 -C 8 alkyl, optionally substituted by 1 to 3 substituents selected from R b respectively; and Ry及Rz为： Ry and Rz are: (a)分别为氢、C1-C8烷基、C2-C8烯基、C2-C8炔基、C6-C10芳基C1-C8烷基、C2-C8烷基醚、C1-C8烷氧基、4元至10元碳环或杂环，或接合至Rc而形成一个4元至10元碳环或杂环，其中各个Ry及Rz分别为未经取代或被1至9个分别选自Rb的取代基取代；或(a) hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 6 -C 10 aryl, C 1 -C 8 alkyl, C 2 -C 8 alkyl ether, C 1 -C 8 alkoxy, 4 to 10 membered carbocyclic or heterocyclic ring, or joined to R c to form a 4 to 10 membered carbocyclic or heterocyclic ring, wherein each of R y and R z are each unsubstituted or substituted by 1 to 9 substituents respectively selected from R b ; or (b)接合而形成一个4元至10元碳环或杂环，其为未经取代或被1至9个分别选自Rb的取代基取代；(b) joined to form a 4- to 10-membered carbocyclic or heterocyclic ring, which is unsubstituted or substituted by 1 to 9 substituents selected from R respectively; Ar1及Ar2分别是选自5元至10元芳香族碳环及杂环，其各自为未经取代或被1至3个分别选自式LRa群组的取代基取代；Ar 1 and Ar 2 are respectively selected from 5-membered to 10-membered aromatic carbocyclic rings and heterocyclic rings, each of which is unsubstituted or substituted by 1 to 3 substituents selected from the group of formula LRa ; L在各自出现时分别是选自键连接、-O-、-C(＝O)-、-OC(＝O)-、-C(＝O)O-、-O-C(＝O)O-、-S(O)m-、-NRx-、-C(＝O)NHRx-、-NHRxC(＝O)-、-NRxS(O)m-、S(O)mNRx-及-N[S(O)mRx]S(O)m-；其中m在各自出现时分别是选自0、1及2；以及Rx在各次出现时分别是选自氢及C1-C8烷基；L is selected from bond linkage, -O-, -C(=O)-, -OC(=O)-, -C(=O)O-, -OC(=O)O-, -OC(=O)O-, -S(O) m -, -NR x -, -C(=O)NHR x -, -NHR x C(=O)-, -NR x S(O) m -, S(O) m NR x - and -N[S(O) m R x ]S(O) m -; wherein m at each occurrence is selected from 0, 1 and 2; and R x at each occurrence is selected from hydrogen and C 1 -C 8 alkyl; Ra在各次出现时分别是选自：R a at each occurrence is selected from: (i)氢、卤原子、氰基及硝基；以及(i) hydrogen, halogen, cyano and nitro; and (ii)C1-C8烷基、C2-C8烯基、C2-C8炔基、C2-C8烷基醚、3元至10元杂环、一-(C1-C8烷基)氨基及二-(C1-C8烷基)氨基及(3元至10元杂环)C1-C6烷基，其各自为未经取代或被1至9个分别选自Rb的取代基取代；以及(ii) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 2 -C 8 alkyl ether, 3- to 10-membered heterocycle, one-(C 1 - C 8 alkyl) amino and di-(C 1 -C 8 alkyl) amino and (3-membered to 10-membered heterocycle) C 1 -C 6 alkyl, each of which is unsubstituted or replaced by 1 to 9, respectively is substituted with a substituent selected from R b ; and Rb在各次出现时分别是选自羟基、卤原子、氨基、氨基羰基、酰氨基、氰基、硝基、酮基、C1-C8烷基、C1-C8烷氧基、C1-C8烷硫基、C1-C8烷基醚、羟基C1-C8烷基、卤基C1-C8烷基、苯基、苯基(C1-C8烷基)、一-(C1-C6烷基)氨基及二-(C1-C6烷基)氨基、(SO2)C1-C8烷基、5元至7元杂环及(5元至7元杂环)(C1-C8烷基)；R b is selected from hydroxyl, halogen atom, amino, aminocarbonyl, amido, cyano, nitro, ketone, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, C 1 -C 8 alkyl ether, hydroxy C 1 -C 8 alkyl, halo C 1 -C 8 alkyl, phenyl, phenyl (C 1 -C 8 alkyl ), one-(C 1 -C 6 alkyl) amino and di-(C 1 -C 6 alkyl) amino, (SO 2 ) C 1 -C 8 alkyl, 5- to 7-membered heterocycle and (5 7-membered heterocycle) (C 1 -C 8 alkyl); 以及由此促进患者的体重减轻。and thereby promote weight loss in the patient. 112.如权利要求111所述的方法，其中该化合物为如权利要求1、16、34或61中任一所述的化合物。112. The method of claim 111, wherein the compound is the compound of any one of claims 1, 16, 34, or 61. 113.如权利要求1、16、34或61中任一所述的化合物或盐，其中所述化合物或盐是经放射性标记。113. The compound or salt of any one of claims 1, 16, 34, or 61, wherein the compound or salt is radiolabeled. 114、一种测定在样品中是否存在有辣椒辣素受体的方法，包含下列步骤：114. A method of determining the presence or absence of capsaicin receptors in a sample comprising the steps of: (a)让该样品在允许化合物结合至辣椒辣素受体的条件下，接触如权利要求1、16、34或61中任一所述的化合物或盐；以及(a) contacting the sample with the compound or salt of any one of claims 1, 16, 34 or 61 under conditions that allow the compound to bind to the capsaicin receptor; and (b)检测化合物结合至辣椒辣素受体的程度，以及由此测定样品中是否存在有辣椒辣素受体。(b) detecting the extent to which the compound binds to the capsaicin receptor, and thereby determining the presence or absence of the capsaicin receptor in the sample. 115.如权利要求114所述的方法，其中该化合物为如权利要求113所述的放射性标记化合物，以及其中该检测步骤包含下列步骤：115. The method of claim 114, wherein the compound is the radiolabeled compound of claim 113, and wherein the detecting step comprises the steps of: (i)将未结合的化合物由结合的化合物分开；以及(i) separating unbound compounds from bound compounds; and (ii)检测样品内是否存在有结合的化合物。(ii) Detecting the presence of bound compounds in the sample. 116、一种包装的医药制剂，包含：116. A packaged pharmaceutical preparation comprising: (a)在一容器中的如权利要求81所述的医药组合物；以及(a) the pharmaceutical composition of claim 81 in a container; and (b)使用该组合物治疗疼痛的指示。(b) Instructions for using the composition to treat pain. 117、一种包装的医药制剂，包含：117. A packaged pharmaceutical preparation comprising: (a)在一容器中的如权利要求81所述的医药组合物；以及(a) the pharmaceutical composition of claim 81 in a container; and (b)使用该组合物治疗咳嗽或打嗝的指示。(b) Instructions for using the composition to treat cough or hiccups. 118、一种包装的医药制剂，包含：118. A packaged pharmaceutical formulation comprising: (a)在一容器中的如权利要求81所述的医药组合物；以及(a) the pharmaceutical composition of claim 81 in a container; and (b)使用该组合物治疗肥胖的指示。(b) Indications for using the composition to treat obesity. 119、一种如权利要求1、16、34或61中任一所述的化合物，用于制造药物来治疗患者对辣椒辣素受体调节有反应性的病情的用途。119. Use of a compound as claimed in any one of claims 1, 16, 34 or 61 for the manufacture of a medicament for the treatment of a condition in a patient responsive to capsaicin receptor modulation. 120.如权利要求119所述的用途，其中该病情是选自烧烫伤、疼痛、搔痒、咳嗽、打嗝或支气管缩窄。120. The use of claim 119, wherein the condition is selected from burns, pain, itching, coughing, hiccups or bronchoconstriction.
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